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Kręcisz P, Stefańska K, Studziński J, Pitucha M, Czylkowska A, Szymański P. Radiocopper in Radiopharmacy and Medical Use: Current Status and Perspective. J Med Chem 2025; 68:2356-2376. [PMID: 39895089 PMCID: PMC11831595 DOI: 10.1021/acs.jmedchem.4c02885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 01/21/2025] [Accepted: 01/27/2025] [Indexed: 02/04/2025]
Abstract
Of the 32 known copper isotopes, some have interesting properties for nuclear medicine, for example the short-lived 60Cu, 61Cu, 62Cu, the moderate long-lived 64Cu and the long-lived 67Cu. Due to their emission properties, copper isotopes are suitable for both imaging diagnostics (60Cu, 61Cu, 62Cu, 64Cu) and targeted radiotherapy (64Cu and 67Cu). As their chemical properties are virtually identical, a single radiopharmaceutical structure can be labeled with different isotopes, depending on the clinical application. This, combined with the ability to combine radioisotopes with different nuclear properties with the same ligand, makes them extremely versatile. The purpose of this review is to introduce the world of copper radiopharmaceuticals and to summarize recent advances in methods for producing copper radioisotopes and the preclinical research of radiopharmaceuticals labeled with copper radioisotopes.
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Affiliation(s)
- Paweł Kręcisz
- Department
of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty
of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland
| | - Katarzyna Stefańska
- Department
of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty
of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland
| | - Jakub Studziński
- Department
of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty
of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland
| | - Monika Pitucha
- Independent
Radiopharmacy Unit, Faculty of Pharmacy, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland
| | - Agnieszka Czylkowska
- Institute
of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland
| | - Paweł Szymański
- Department
of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty
of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland
- Department
of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, Kozielska 4, 01-163 Warsaw, Poland
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2
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Koniar H, McNeil S, Wharton L, Ingham A, Van de Voorde M, Ooms M, Sekar S, Rodríguez-Rodríguez C, Kunz P, Radchenko V, Rahmim A, Uribe C, Yang H, Schaffer P. Quantitative SPECT imaging of 155Tb and 161Tb for preclinical theranostic radiopharmaceutical development. EJNMMI Phys 2024; 11:77. [PMID: 39276263 PMCID: PMC11401819 DOI: 10.1186/s40658-024-00682-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 09/04/2024] [Indexed: 09/16/2024] Open
Abstract
BACKGROUND Element-equivalent matched theranostic pairs facilitate quantitative in vivo imaging to establish pharmacokinetics and dosimetry estimates in the development of preclinical radiopharmaceuticals. Terbium radionuclides have significant potential as matched theranostic pairs for multipurpose applications in nuclear medicine. In particular, 155Tb (t1/2 = 5.32 d) and 161Tb (t1/2 = 6.89 d) have been proposed as a theranostic pair for their respective applications in single photon emission computed tomography (SPECT) imaging and targeted beta therapy. Our study assessed the performance of preclinical quantitative SPECT imaging with 155Tb and 161Tb. A hot rod resolution phantom with rod diameters ranging between 0.85 and 1.70 mm was filled with either 155Tb (21.8 ± 1.7 MBq/mL) or 161Tb (23.6 ± 1.9 MBq/mL) and scanned with the VECTor preclinical SPECT/CT scanner. Image performance was evaluated with two collimators: a high energy ultra high resolution (HEUHR) collimator and an extra ultra high sensitivity (UHS) collimator. SPECT images were reconstructed from photopeaks at 43.0 keV, 86.6 keV, and 105.3 keV for 155Tb and 48.9 keV and 74.6 keV for 161Tb. Quantitative SPECT images of the resolution phantoms were analyzed to report inter-rod contrast, recovery coefficients, and contrast-to-noise metrics. RESULTS Quantitative SPECT images of the resolution phantom established that the HEUHR collimator resolved all rods for 155Tb and 161Tb, and the UHS collimator resolved rods ≥ 1.10 mm for 161Tb and ≥ 1.30 mm for 155Tb. The HEUHR collimator maintained better quantitative accuracy than the UHS collimator with recovery coefficients up to 92%. Contrast-to-noise metrics were also superior with the HEUHR collimator. CONCLUSIONS Both 155Tb and 161Tb demonstrated potential for applications in preclinical quantitative SPECT imaging. The high-resolution collimator achieves < 0.85 mm resolution and maintains quantitative accuracy in small volumes which is advantageous for assessing sub organ activity distributions in small animals. This imaging method can provide critical quantitative information for assessing and optimizing preclinical Tb-radiopharmaceuticals.
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Affiliation(s)
- Helena Koniar
- TRIUMF, Life Sciences Division, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada.
- Department of Physics and Astronomy, University of British Columbia, 6224 Agricultural Road, Vancouver, BC, CAN V6T, Canada.
| | - Scott McNeil
- TRIUMF, Life Sciences Division, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada
| | - Luke Wharton
- TRIUMF, Life Sciences Division, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada
| | - Aidan Ingham
- TRIUMF, Life Sciences Division, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada
| | - Michiel Van de Voorde
- Institute for Nuclear Medical Applications Science, SCK CEN, Boeretang 200, Mol, BE, 2400, Canada
| | - Maarten Ooms
- Institute for Nuclear Medical Applications Science, SCK CEN, Boeretang 200, Mol, BE, 2400, Canada
| | - Sathiya Sekar
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Cristina Rodríguez-Rodríguez
- Department of Physics and Astronomy, University of British Columbia, 6224 Agricultural Road, Vancouver, BC, CAN V6T, Canada
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Peter Kunz
- TRIUMF, Accelerator Division, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada
- Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada
| | - Valery Radchenko
- TRIUMF, Life Sciences Division, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada
- Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada
| | - Arman Rahmim
- Department of Physics and Astronomy, University of British Columbia, 6224 Agricultural Road, Vancouver, BC, CAN V6T, Canada
- Department of Radiology, University of British Columbia, 2775 Laurel Street, Vancouver, BC, V5Z 1M9, Canada
- BC Cancer Research Centre, Department of Integrative Oncology, 675 W 10th Ave, Vancouver, BC, V5Z 1L3, Canada
| | - Carlos Uribe
- Department of Radiology, University of British Columbia, 2775 Laurel Street, Vancouver, BC, V5Z 1M9, Canada
- BC Cancer Research Centre, Department of Integrative Oncology, 675 W 10th Ave, Vancouver, BC, V5Z 1L3, Canada
- Functional Imaging, BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada
| | - Hua Yang
- TRIUMF, Life Sciences Division, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada
- Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada
| | - Paul Schaffer
- TRIUMF, Life Sciences Division, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada
- Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada
- Department of Radiology, University of British Columbia, 2775 Laurel Street, Vancouver, BC, V5Z 1M9, Canada
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3
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Bowden G, Scott PJH, Boros E. Radiochemistry: A Hot Field with Opportunities for Cool Chemistry. ACS CENTRAL SCIENCE 2023; 9:2183-2195. [PMID: 38161375 PMCID: PMC10755734 DOI: 10.1021/acscentsci.3c01050] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 10/20/2023] [Accepted: 10/24/2023] [Indexed: 01/03/2024]
Abstract
Recent Food and Drug Administration (FDA) approval of diagnostic and therapeutic radiopharmaceuticals and concurrent miniaturization of particle accelerators leading to improved access has fueled interest in the development of chemical transformations suitable for short-lived radioactive isotopes on the tracer scale. This recent renaissance of radiochemistry is paired with new opportunities to study fundamental chemical behavior and reactivity of elements to improve their production, separation, and incorporation into bioactive molecules to generate new radiopharmaceuticals. This outlook outlines pertinent challenges in the field of radiochemistry and indicates areas of opportunity for chemical discovery and development, including those of clinically established (C-11, F-18) and experimental radionuclides in preclinical development across the periodic table.
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Affiliation(s)
- Gregory
D. Bowden
- Department
of Radiology, University of Michigan, 1301 Catherine, Ann Arbor, Michigan 48109, United States
- Werner
Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tuebingen, 72074 Tuebingen, Germany
- Cluster
of Excellence iFIT (EXC 2180) “Image Guided and Functionally
Instructed Tumor Therapies”, Eberhard
Karls University of Tuebingen, 72074 Tuebingen, Germany
| | - Peter J. H. Scott
- Department
of Radiology, University of Michigan, 1301 Catherine, Ann Arbor, Michigan 48109, United States
| | - Eszter Boros
- Department
of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, Wisconsin 53706, United States
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Rowan JA, Rudd SE, Ganio K, McDevitt CA, White JM, Donnelly PS. Copper(II) Complexes of 2,2'- Bisdipyrrins: Synthesis, Characterization, Cell Uptake, and Radiolabeling with Copper-64. Inorg Chem 2023; 62:20666-20676. [PMID: 37552883 DOI: 10.1021/acs.inorgchem.3c01551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
Complexes prepared with positron-emitting copper-64 are of interest as imaging agents for positron emission tomography (PET). This work investigates the potential of using acyclic tetrapyrrolic 2,2'-bisdipyrrins as ligands to prepare charge-neutral, lipophilic, cell-permeable, redox active complexes with positron-emitting copper-64. The synthesis and characterization of a series of tetrapyrrolic 2,2'-bisdipyrrin copper(II) complexes are reported. Four 2,2'-bisdipyrrin copper(II) complexes were prepared with different functional groups in the meso-position of the ligands. Two of the new copper(II) complexes, one palladium(II) complex, and one nickel(II) complex were characterized by X-ray crystallography, which demonstrated that the copper(II) is in a distorted square planar environment. An investigation of the electrochemical properties of the complexes by cyclic voltammetry revealed that the complexes undergo multiple quasi-reversible processes. A comparison of the cyclic voltammetry of the copper complexes with their palladium(II) analogues suggests that these redox processes are ligand-based and not metal-based. The copper(II) complexes are cell-permeable in A431 mammalian cells and are nontoxic at concentrations of 50 μM. The ligands can be radiolabeled with copper-64 at room temperature.
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Affiliation(s)
- Jacob A Rowan
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Stacey E Rudd
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Katherine Ganio
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3000, Australia
| | - Christopher A McDevitt
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3000, Australia
| | - Jonathan M White
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Paul S Donnelly
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia
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5
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Tosato M, Franchi S, Isse AA, Del Vecchio A, Zanoni G, Alker A, Asti M, Gyr T, Di Marco V, Mäcke H. Is Smaller Better? Cu 2+/Cu + Coordination Chemistry and Copper-64 Radiochemical Investigation of a 1,4,7-Triazacyclononane-Based Sulfur-Rich Chelator. Inorg Chem 2023; 62:20621-20633. [PMID: 37115633 PMCID: PMC10731632 DOI: 10.1021/acs.inorgchem.3c00621] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Indexed: 04/29/2023]
Abstract
The biologically triggered reduction of Cu2+ to Cu+ has been postulated as a possible in vivo decomplexation pathway in 64/67Cu-based radiopharmaceuticals. In an attempt to hinder this phenomenon, we have previously developed a family of S-containing polyazamacrocycles based on 12-, 13-, or 14-membered tetraaza rings able to stabilize both oxidation states. However, despite the high thermodynamic stability of the resulting Cu2+/+ complexes, a marked [64Cu]Cu2+ release was detected in human serum, likely as a result of the partially saturated coordination sphere around the copper center. In the present work, a new hexadentate macrocyclic ligand, 1,4,7-tris[2-(methylsulfanyl)ethyl)]-1,4,7-triazacyclononane (NO3S), was synthesized by hypothesizing that a smaller macrocyclic backbone could thwart the observed demetalation by fully encapsulating the copper ion. To unveil the role of the S donors in the metal binding, the corresponding alkyl analogue 1,4,7-tris-n-butyl-1,4,7-triazacyclononane (TACN-n-Bu) was considered as comparison. The acid-base properties of the free ligands and the kinetic, thermodynamic, and structural properties of their Cu2+ and Cu+ complexes were investigated in solution and solid (crystal) states through a combination of spectroscopic and electrochemical techniques. The formation of two stable mononuclear species was detected in aqueous solution for both ligands. The pCu2+ value for NO3S at physiological pH was 6 orders of magnitude higher than that computed for TACN-n-Bu, pointing out the significant stabilizing contribution arising from the Cu2+-S interactions. In both the solid state and solution, Cu2+ was fully embedded in the ligand cleft in a hexacoordinated N3S3 environment. Furthermore, NO3S exhibited a remarkable ability to form a stable complex with Cu+ through the involvement of all of the donors in the coordination sphere. Radiolabeling studies evidenced an excellent affinity of NO3S toward [64Cu]Cu2+, as quantitative incorporation was achieved at high apparent molar activity (∼10 MBq/nmol) and under mild conditions (ambient temperature, neutral pH, 10 min reaction time). Human serum stability assays revealed an increased stability of [64Cu][Cu(NO3S)]2+ when compared to the corresponding complexes formed by 12-, 13-, or 14-membered tetraaza rings.
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Affiliation(s)
- Marianna Tosato
- Department
of Chemical Sciences, University of Padova, 35131 Padova, Italy
| | - Sara Franchi
- Department
of Chemical Sciences, University of Padova, 35131 Padova, Italy
| | | | | | - Giordano Zanoni
- Department
of Chemical Sciences, University of Padova, 35131 Padova, Italy
| | - André Alker
- Roche
Pharmaceutical Research and Early Development, Roche Innovation Center Basel F. Hoffmann-La Roche, 4058 Basel, Switzerland
| | - Mattia Asti
- Radiopharmaceutical
Chemistry Section, Nuclear Medicine Unit, AUSL-IRCCS Reggio Emilia, 42122 Reggio Emilia, Italy
| | - Thomas Gyr
- Division
of Radiopharmaceutical Chemistry, Clinic of Radiology and Nuclear
Medicine, University Hospital Basel, 4031 Basel, Switzerland
| | - Valerio Di Marco
- Department
of Chemical Sciences, University of Padova, 35131 Padova, Italy
| | - Helmut Mäcke
- Department
of Nuclear Medicine, University Hospital
Freiburg, D-79106 Freiburg, Germany
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6
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Hierlmeier I, Guillou A, Earley DF, Linden A, Holland JP, Bartholomä MD. HNODThia: A Promising Chelator for the Development of 64Cu Radiopharmaceuticals. Inorg Chem 2023; 62:20677-20687. [PMID: 37487036 DOI: 10.1021/acs.inorgchem.3c01616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
Herein, we present the synthesis and coordination chemistry of copper(II) and zinc(II) complexes of two novel heterocyclic triazacyclononane (tacn)-based chelators (HNODThia and NODThia-AcNHEt). The chelator HNODThia was further derivatized to obtain a novel PSMA-based bioconjugate (NODThia-PSMA) and a bifunctional photoactivatable azamacrocyclic analogue, NODThia-PEG3-ArN3, for the development of copper-64 radiopharmaceuticals. 64Cu radiolabeling experiments were performed on the different metal-binding chelates, whereby quantitative radiochemical conversion (RCC) was obtained in less than 10 min at room temperature. The in vitro stability of NODThia-PSMA in human plasma was assessed by ligand-challenge and copper-exchange experiments. Next, we investigated the viability of the photoactivatable analog (NODThia-PEG3-ArN3) for the light-induced photoradiosynthesis of radiolabeled proteins. One-pot photoconjugation reactions to human serum albumin (HSA) as a model protein and the clinically relevant monoclonal antibody formulation MetMAb were performed. [64Cu]Cu-7-azepin-HSA and [64Cu]Cu-7-azepin-onartuzumab were prepared in less than 15 min by irradiation at 395 nm, with radiochemical purities (RCP) of >95% and radiochemical yields (RCYs) of 42.7 ± 5.3 and 49.6%, respectively. Together, the results obtained here open the way for the development of highly stable 64Cu-radiopharmaceuticals by using aza-heterocyclic tacn-based chelators, and the method can easily be extended to the development of 67Cu radiopharmaceuticals for future applications in molecularly targeted radio(immuno)therapy.
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Affiliation(s)
- Ina Hierlmeier
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrberger Str. 100, Building 50, 66421 Homburg, Germany
| | - Amaury Guillou
- University of Zurich, Department of Chemistry, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
- University of Caen, Cyceron, Bd Henri Becquerel, 14000 Caen, France
| | - Daniel F Earley
- University of Zurich, Department of Chemistry, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
| | - Anthony Linden
- University of Zurich, Department of Chemistry, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
| | - Jason P Holland
- University of Zurich, Department of Chemistry, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
| | - Mark D Bartholomä
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrberger Str. 100, Building 50, 66421 Homburg, Germany
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7
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Fani M, Nicolas GP. 61Cu-Labeled Radiotracers: Alternative or Choice? J Nucl Med 2023; 64:1855-1857. [PMID: 37884329 PMCID: PMC10690116 DOI: 10.2967/jnumed.123.266171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/05/2023] [Indexed: 10/28/2023] Open
Affiliation(s)
- Melpomeni Fani
- Division of Radiopharmaceutical Chemistry, University Hospital Basel, Basel, Switzerland; and
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8
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Morgan KA, Rudd SE, Noor A, Donnelly PS. Theranostic Nuclear Medicine with Gallium-68, Lutetium-177, Copper-64/67, Actinium-225, and Lead-212/203 Radionuclides. Chem Rev 2023; 123:12004-12035. [PMID: 37796539 DOI: 10.1021/acs.chemrev.3c00456] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2023]
Abstract
Molecular changes in malignant tissue can lead to an increase in the expression levels of various proteins or receptors that can be used to target the disease. In oncology, diagnostic imaging and radiotherapy of tumors is possible by attaching an appropriate radionuclide to molecules that selectively bind to these target proteins. The term "theranostics" describes the use of a diagnostic tool to predict the efficacy of a therapeutic option. Molecules radiolabeled with γ-emitting or β+-emitting radionuclides can be used for diagnostic imaging using single photon emission computed tomography or positron emission tomography. Radionuclide therapy of disease sites is possible with either α-, β-, or Auger-emitting radionuclides that induce irreversible damage to DNA. This Focus Review centers on the chemistry of theranostic approaches using metal radionuclides for imaging and therapy. The use of tracers that contain β+-emitting gallium-68 and β-emitting lutetium-177 will be discussed in the context of agents in clinical use for the diagnostic imaging and therapy of neuroendocrine tumors and prostate cancer. A particular emphasis is then placed on the chemistry involved in the development of theranostic approaches that use copper-64 for imaging and copper-67 for therapy with functionalized sarcophagine cage amine ligands. Targeted therapy with radionuclides that emit α particles has potential to be of particular use in late-stage disease where there are limited options, and the role of actinium-225 and lead-212 in this area is also discussed. Finally, we highlight the challenges that impede further adoption of radiotheranostic concepts while highlighting exciting opportunities and prospects.
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Affiliation(s)
- Katherine A Morgan
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Stacey E Rudd
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Asif Noor
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Paul S Donnelly
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne 3010, Australia
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9
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Calatayud DG, Lledos M, Casarsa F, Pascu SI. Functional Diversity in Radiolabeled Nanoceramics and Related Biomaterials for the Multimodal Imaging of Tumors. ACS BIO & MED CHEM AU 2023; 3:389-417. [PMID: 37876497 PMCID: PMC10591303 DOI: 10.1021/acsbiomedchemau.3c00021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 07/18/2023] [Accepted: 07/18/2023] [Indexed: 10/26/2023]
Abstract
Nanotechnology advances have the potential to assist toward the earlier detection of diseases, giving increased accuracy for diagnosis and helping to personalize treatments, especially in the case of noncommunicative diseases (NCDs) such as cancer. The main advantage of nanoparticles, the scaffolds underpinning nanomedicine, is their potential to present multifunctionality: synthetic nanoplatforms for nanomedicines can be tailored to support a range of biomedical imaging modalities of relevance for clinical practice, such as, for example, optical imaging, computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). A single nanoparticle has the potential to incorporate myriads of contrast agent units or imaging tracers, encapsulate, and/or be conjugated to different combinations of imaging tags, thus providing the means for multimodality diagnostic methods. These arrangements have been shown to provide significant improvements to the signal-to-noise ratios that may be obtained by molecular imaging techniques, for example, in PET diagnostic imaging with nanomaterials versus the cases when molecular species are involved as radiotracers. We surveyed some of the main discoveries in the simultaneous incorporation of nanoparticulate materials and imaging agents within highly kinetically stable radio-nanomaterials as potential tracers with (pre)clinical potential. Diversity in function and new developments toward synthesis, radiolabeling, and microscopy investigations are explored, and preclinical applications in molecular imaging are highlighted. The emphasis is on the biocompatible materials at the forefront of the main preclinical developments, e.g., nanoceramics and liposome-based constructs, which have driven the evolution of diagnostic radio-nanomedicines over the past decade.
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Affiliation(s)
- David G. Calatayud
- Department
of Inorganic Chemistry, Universidad Autónoma
de Madrid, Madrid 28049, Spain
- Department
of Electroceramics, Instituto de Cerámica
y Vidrio, Madrid 28049, Spain
| | - Marina Lledos
- Department
of Chemistry, University of Bath, Bath BA2 7AY, United Kingdom
| | - Federico Casarsa
- Department
of Chemistry, University of Bath, Bath BA2 7AY, United Kingdom
| | - Sofia I. Pascu
- Department
of Chemistry, University of Bath, Bath BA2 7AY, United Kingdom
- Centre
of Therapeutic Innovations, University of
Bath, Bath BA2 7AY, United Kingdom
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10
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Hussain M, Qaim SM, Spahn I, Aslam MN, Neumaier B. Copper radionuclides for theranostic applications: towards standardisation of their nuclear data. A mini-review. Front Chem 2023; 11:1270351. [PMID: 37841203 PMCID: PMC10570421 DOI: 10.3389/fchem.2023.1270351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 09/08/2023] [Indexed: 10/17/2023] Open
Abstract
Copper has several clinically relevant radioisotopes and versatile coordination chemistry, allowing attachment of its radionuclides to biological molecules. This characteristic makes it suitable for applications in molecular imaging or radionuclide targeted therapy. Of particular interest in nuclear medicine today is the theranostic approach. This brief review considers five radionuclides of copper. These are Cu-60, Cu-61, Cu-62, Cu-64, and Cu-67. The first four are positron emitters for imaging, and the last one Cu-67 is a β--emitting radionuclide suitable for targeted therapy. The emphasis here is on theory-aided evaluation of available experimental data with a view to establishing standardised cross-section database for production of the relevant radionuclide in high purity. Evaluated cross section data of the positron emitters have been already extensively reported; so here they are only briefly reviewed. More attention is given to the data of the 68Zn(p,2p)67Cu intermediate energy reaction which is rather commonly used for production of 67Cu.
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Affiliation(s)
- Mazhar Hussain
- Institut für Neurowissenschaften und Medizin, INM-5: Nuklearchemie, Forschungszentrum Jülich (FZJ), Jülich, Germany
- Department of Physics, Government College University Lahore (GCUL), Lahore, Pakistan
| | - Syed M. Qaim
- Institut für Neurowissenschaften und Medizin, INM-5: Nuklearchemie, Forschungszentrum Jülich (FZJ), Jülich, Germany
| | - Ingo Spahn
- Institut für Neurowissenschaften und Medizin, INM-5: Nuklearchemie, Forschungszentrum Jülich (FZJ), Jülich, Germany
| | - M. Naveed Aslam
- Department of Physics, COMSATS University Islamabad, Lahore, Pakistan
| | - Bernd Neumaier
- Institut für Neurowissenschaften und Medizin, INM-5: Nuklearchemie, Forschungszentrum Jülich (FZJ), Jülich, Germany
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Dellepiane G, Casolaro P, Mateu I, Scampoli P, Braccini S. Alternative routes for 64Cu production using an 18 MeV medical cyclotron in view of theranostic applications. Appl Radiat Isot 2023; 191:110518. [DOI: 10.1016/j.apradiso.2022.110518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/28/2022]
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12
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Eom S, Kim MH, Yoo R, Choi G, Kang JH, Lee YJ, Choy JH. Dilute lattice doping of 64Cu into 2D-nanoplates: its impact on radio-labeling efficiency and stability for target selective PET imaging. J Mater Chem B 2022; 10:9389-9399. [PMID: 35929536 DOI: 10.1039/d2tb01165d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
A quintinite nanoplate (64Cu-QT-NP) isomorphically substituted with 64Cu, as the positron emission tomography (PET) imaging material, was prepared via two-step processes. A 64Cu labeling efficiency of 99% was realized, for the first time, by immobilizing the 64Cu radioisotope directly in the octahedral site of the 2-dimensional (2D) quintinite lattice. Furthermore, the 64Cu labeling stability of 64Cu-QT-NPs was also achieved to be more than ∼99% in various solutions such as saline, phosphate-buffered saline (PBS), and other biological media (mouse and human serums). In an in vivo xenograft mouse model, the passive targeting behavior of 64Cu-QT-NPs into tumor tissue based on the enhanced permeability and retention (EPR) effect was also demonstrated by parenteral administration, and successfully visualized using a PET scanner. For enhancing the tumor tissue selectivity, bovine serum albumin (BSA) was coated on 64Cu-QT-NPs to form 64Cu-QT-NPs/BSA, resulting in better colloidal stability and longer blood circulation time, which was eventually evidenced by the 2-fold higher tumor uptake rate when intravenousely injected in an animal model. It is, therefore, concluded that the present 64Cu-QT-NPs/BSA with tumor tissue selectivity could be an advanced nano-device for radio-imaging and diagnosis as well.
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Affiliation(s)
- Sairan Eom
- Center for Intelligent Nano-Bio Materials (CINBM), Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Republic of Korea.,Division of Applied-RI, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
| | - Min Hwan Kim
- Division of Applied-RI, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
| | - Ranji Yoo
- Division of Applied-RI, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
| | - Goeun Choi
- Intelligent Nanohybrid Materials Laboratory (INML), Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Republic of Korea. .,College of Science and Technology, Dankook University, Cheonan 31116, Republic of Korea.,Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea
| | - Joo Hyun Kang
- Division of Applied-RI, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
| | - Yong Jin Lee
- Division of Applied-RI, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
| | - Jin-Ho Choy
- Intelligent Nanohybrid Materials Laboratory (INML), Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Republic of Korea. .,Department of Pre-medical Course, College of Medicine, Dankook University, Cheonan 31116, Republic of Korea.,International Research Frontier Initiative (IRFI), Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan
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13
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Dellepiane G, Casolaro P, Mateu I, Scampoli P, Voeten N, Braccini S. Cross-section measurement for an optimized 61Cu production at an 18 MeV medical cyclotron from natural Zn and enriched 64Zn solid targets. Appl Radiat Isot 2022; 190:110466. [PMID: 36174333 DOI: 10.1016/j.apradiso.2022.110466] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/25/2022] [Accepted: 09/14/2022] [Indexed: 11/25/2022]
Abstract
The availability of novel medical radionuclides is a key point in the development of personalised nuclear medicine. In particular, copper radioisotopes are attracting considerable interest as they can be used to label various molecules of medical interest, such as proteins and peptides, and offer two of the most promising true theranostic pairs, namely 61Cu/67Cu and 64Cu/67Cu. Although 64Cu (t1/2 = 12.7006 h, β+: 17.6%, β-: 38.5%) is nowadays the most commonly used as a diagnostic radionuclide, 61Cu (t1/2 = 3.339 h, β+: 61%) features more favourable nuclear properties, such as a higher positron decay fraction and the absence of β- emissions. To date, the production of 61Cu has been carried out irradiating highly enriched 61Ni targets with a low energy proton beam. However, the use of the very expensive 61Ni targets requires an efficient recovery of the target material and makes this method quite inconvenient. Another promising production route is the proton irradiation of natural Zn or enriched 64Zn targets, exploiting the (p,α) nuclear reaction. Along this line, a research program is ongoing at the Bern medical cyclotron, equipped with an external beam transfer line and a solid target station. In this paper, we report on cross-section measurements of the 64Zn(p,α)61Cu nuclear reaction using natural Zn and enriched 64Zn material, which served as the basis to perform optimized 61Cu production tests with solid targets.
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Affiliation(s)
- Gaia Dellepiane
- Albert Einstein Center for Fundamental Physics (AEC), Laboratory for High Energy Physics (LHEP), University of Bern, Sidlerstrasse 5, CH-3012 Bern, Switzerland.
| | - Pierluigi Casolaro
- Albert Einstein Center for Fundamental Physics (AEC), Laboratory for High Energy Physics (LHEP), University of Bern, Sidlerstrasse 5, CH-3012 Bern, Switzerland
| | - Isidre Mateu
- Albert Einstein Center for Fundamental Physics (AEC), Laboratory for High Energy Physics (LHEP), University of Bern, Sidlerstrasse 5, CH-3012 Bern, Switzerland
| | - Paola Scampoli
- Albert Einstein Center for Fundamental Physics (AEC), Laboratory for High Energy Physics (LHEP), University of Bern, Sidlerstrasse 5, CH-3012 Bern, Switzerland; Department of Physics "Ettore Pancini", University of Napoli Federico II, Complesso Universitario di Monte S. Angelo, 80126 Napoli, Italy
| | - Naomi Voeten
- Albert Einstein Center for Fundamental Physics (AEC), Laboratory for High Energy Physics (LHEP), University of Bern, Sidlerstrasse 5, CH-3012 Bern, Switzerland
| | - Saverio Braccini
- Albert Einstein Center for Fundamental Physics (AEC), Laboratory for High Energy Physics (LHEP), University of Bern, Sidlerstrasse 5, CH-3012 Bern, Switzerland
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14
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Chelation of Theranostic Copper Radioisotopes with S-Rich Macrocycles: From Radiolabelling of Copper-64 to In Vivo Investigation. Molecules 2022; 27:molecules27134158. [PMID: 35807404 PMCID: PMC9268100 DOI: 10.3390/molecules27134158] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 12/10/2022] Open
Abstract
Copper radioisotopes are generally employed for cancer imaging and therapy when firmly coordinated via a chelating agent coupled to a tumor-seeking vector. However, the biologically triggered Cu2+-Cu+ redox switching may constrain the in vivo integrity of the resulting complex, leading to demetallation processes. This unsought pathway is expected to be hindered by chelators bearing N, O, and S donors which appropriately complements the borderline-hard and soft nature of Cu2+ and Cu+. In this work, the labelling performances of a series of S-rich polyazamacrocyclic chelators with [64Cu]Cu2+ and the stability of the [64Cu]Cu-complexes thereof were evaluated. Among the chelators considered, the best results were obtained with 1,7-bis [2-(methylsulfanyl)ethyl]-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). DO2A2S was labelled at high molar activities in mild reaction conditions, and its [64Cu]Cu2+ complex showed excellent integrity in human serum over 24 h. Biodistribution studies in BALB/c nude mice performed with [64Cu][Cu(DO2A2S)] revealed a behavior similar to other [64Cu]Cu-labelled cyclen derivatives characterized by high liver and kidney uptake, which could either be ascribed to transchelation phenomena or metabolic processing of the intact complex.
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15
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Gawne P, Man F, Blower PJ, T. M. de Rosales R. Direct Cell Radiolabeling for in Vivo Cell Tracking with PET and SPECT Imaging. Chem Rev 2022; 122:10266-10318. [PMID: 35549242 PMCID: PMC9185691 DOI: 10.1021/acs.chemrev.1c00767] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Indexed: 02/07/2023]
Abstract
The arrival of cell-based therapies is a revolution in medicine. However, its safe clinical application in a rational manner depends on reliable, clinically applicable methods for determining the fate and trafficking of therapeutic cells in vivo using medical imaging techniques─known as in vivo cell tracking. Radionuclide imaging using single photon emission computed tomography (SPECT) or positron emission tomography (PET) has several advantages over other imaging modalities for cell tracking because of its high sensitivity (requiring low amounts of probe per cell for imaging) and whole-body quantitative imaging capability using clinically available scanners. For cell tracking with radionuclides, ex vivo direct cell radiolabeling, that is, radiolabeling cells before their administration, is the simplest and most robust method, allowing labeling of any cell type without the need for genetic modification. This Review covers the development and application of direct cell radiolabeling probes utilizing a variety of chemical approaches: organic and inorganic/coordination (radio)chemistry, nanomaterials, and biochemistry. We describe the key early developments and the most recent advances in the field, identifying advantages and disadvantages of the different approaches and informing future development and choice of methods for clinical and preclinical application.
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Affiliation(s)
- Peter
J. Gawne
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ Hospital, London, SE1 7EH, U.K.
| | - Francis Man
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ Hospital, London, SE1 7EH, U.K.
- Institute
of Pharmaceutical Science, School of Cancer
and Pharmaceutical Sciences, King’s College London, London, SE1 9NH, U.K.
| | - Philip J. Blower
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ Hospital, London, SE1 7EH, U.K.
| | - Rafael T. M. de Rosales
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ Hospital, London, SE1 7EH, U.K.
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16
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An overview of nuclear data standardisation work for accelerator-based production of medical radionuclides in Pakistan. RADIOCHIM ACTA 2022. [DOI: 10.1515/ract-2022-0012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Abstract
The standardisation of nuclear reaction cross section data is an integral part of optimisation of production routes of medical radionuclides. The production cross sections are available for the reactor and cyclotron produced radionuclides to be used for diagnostics or therapeutic procedures. The types of nuclear data needed, and the sources of their availability are summarized. The method of standardisation of charged-particle data is briefly described. A historical overview of research work in Pakistan in this direction is given. Examples of a few medically important radionuclides, such as 64Cu, 86Y, 89Zr, 103Pd, 186Re, etc., whose data were standardised and evaluated are highlighted. Calculated thick target yields from the recommended data are given. Some new directions in the nuclear data research are outlined.
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17
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Yousuf I, Bashir M, Arjmand F, Tabassum S. Advancement of metal compounds as therapeutic and diagnostic metallodrugs: Current frontiers and future perspectives. Coord Chem Rev 2021. [DOI: 10.1016/j.ccr.2021.214104] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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18
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Refardt J, Hofland J, Kwadwo A, Nicolas GP, Rottenburger C, Fani M, Wild D, Christ E. Theranostics in neuroendocrine tumors: an overview of current approaches and future challenges. Rev Endocr Metab Disord 2021; 22:581-594. [PMID: 32495250 DOI: 10.1007/s11154-020-09552-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of tumors, mainly localized in the gastrointestinal system. What characterizes NENs is the expression of hormone receptors on the tumor cell surface, making them accessible for diagnostic and therapeutic approaches (theranostics) using radiolabelled peptides. Somatostatin receptors subtype-two (SST2) play an important role in NENs since they are overexpressed and homogeneously distributed at the surface of the majority of NENs. Accordingly, targeting SST2 for diagnostic and therapeutic purposes has been established. Current research aims at upregulating its expression by epigenetic treatment or improving its targeting via use of alternative radioligands. In addition, recent data suggest a future role of SST antagonists as a diagnostic tool and a potential therapeutic option. Another promising target is the glucagon-like peptide-1 (GLP-1) receptor. Targeting GLP-1R using exendin-4 (GLP-1 analogue) has a high sensitivity for the localization of the often SST2-negative sporadic insulinomas and insulinomas in the context of multiple endocrine neoplasia type-1. Further options for patients with insufficient expression of SST2 involve metaiodobenzylguanidine (MIBG) and the molecular target C-X-C motif chemokine receptor-4 (CXCR4), which have been evaluated for potential theranostic approach in symptomatic NENs or dedifferentiated tumors. Recently, new targets such as the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the fibroblast activation protein (FAP) have been identified in NENs. Finally, minigastrin - a ligand targeting the cholecystokinin-2 (CCK2) receptors in medullary thyroid carcinoma and foregut neuroendocrine tumors - may improve future management of these diseases with currently limited therapeutic options. This review summarises the current approaches and future challenges of diagnostic and therapeutic evaluations in neuroendocrine neoplasms.
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Affiliation(s)
- Julie Refardt
- Department of Internal Medicine, Section of Endocrinology, ENETS Center of Excellence, Erasmus Medical Center, Rotterdam, the Netherlands
- Department of Clinical Research, University of Basel, Basel, Switzerland
| | - Johannes Hofland
- Department of Internal Medicine, Section of Endocrinology, ENETS Center of Excellence, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Antwi Kwadwo
- ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
- Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | - Guillaume P Nicolas
- ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
- Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | - Christof Rottenburger
- ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
- Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | - Melpomeni Fani
- Division of Radiopharmaceutical Chemistry, University Hospital Basel, Basel, Switzerland
| | - Damian Wild
- ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
- Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | - Emanuel Christ
- ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland.
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel, Switzerland.
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19
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Jauregui-Osoro M, De Robertis S, Halsted P, Gould SM, Yu Z, Paul RL, Marsden PK, Gee AD, Fenwick A, Blower PJ. Production of copper-64 using a hospital cyclotron: targetry, purification and quality analysis. Nucl Med Commun 2021; 42:1024-1038. [PMID: 34397988 PMCID: PMC8357037 DOI: 10.1097/mnm.0000000000001422] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 03/09/2021] [Indexed: 12/31/2022]
Abstract
OBJECTIVES To construct and evaluate a 64Cu production system that minimises the amount of costly 64Ni, radionuclidic impurities and nonradioactive metal contamination and maximises radiochemical and radionuclidic purity and molar activity; and to report analytical and quality control methods that can be used within typical PET radiochemistry production facilities to measure metal ion concentrations and radiometal molar activities. METHODS Low volume was ensured by dissolving the irradiated nickel in a low volume of hydrochloric acid (<1 mL) using the concave gold target backing as a reaction vessel in a custom-built target holder. Removal of contaminating 55Co and nonradioactive trace metals was ensured by adding an intermediate hydrochloric acid concentration step during the conventional ion-exchange elution process. The radionuclidic purity of the product was determined by half-life measurements, gamma spectroscopy and ion radiochromatography. Trace metal contamination and molar activity were determined by ion chromatography. RESULTS AND CONCLUSIONS On a small scale, suitable for preclinical research, the process produced typically 3.2 GBq 64Cu in 2 mL solution from 9.4 ± 2.1 mg nickel-64 electroplated onto a gold target backing. The product had high molar activity (121.5 GBq/µmol), was free of trace metal contamination detectable by ion chromatography and has been used for many preclinical and clinical PET imaging applications.
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Affiliation(s)
- Maite Jauregui-Osoro
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Simona De Robertis
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Philip Halsted
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Sarah-May Gould
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Zilin Yu
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Rowena L Paul
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Paul K Marsden
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Antony D Gee
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Andrew Fenwick
- National Physical Laboratory, Teddington, Middlesex, London, UK
| | - Philip J. Blower
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
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20
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Tosato M, Dalla Tiezza M, May NV, Isse AA, Nardella S, Orian L, Verona M, Vaccarin C, Alker A, Mäcke H, Pastore P, Di Marco V. Copper Coordination Chemistry of Sulfur Pendant Cyclen Derivatives: An Attempt to Hinder the Reductive-Induced Demetalation in 64/67Cu Radiopharmaceuticals. Inorg Chem 2021; 60:11530-11547. [PMID: 34279088 PMCID: PMC8389837 DOI: 10.1021/acs.inorgchem.1c01550] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The Cu2+ complexes formed by a series of cyclen derivatives bearing sulfur pendant arms, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis[2-(methylsulfanyl)ethyl]-4,10-diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S), were studied in aqueous solution at 25 °C from thermodynamic and structural points of view to evaluate their potential as chelators for copper radioisotopes. UV-vis spectrophotometric out-of-cell titrations under strongly acidic conditions, direct in-cell UV-vis titrations, potentiometric measurements at pH >4, and spectrophotometric Ag+-Cu2+ competition experiments were performed to evaluate the stoichiometry and stability constants of the Cu2+ complexes. A highly stable 1:1 metal-to-ligand complex (CuL) was found in solution at all pH values for all chelators, and for DO2A2S, protonated species were also detected under acidic conditions. The structures of the Cu2+ complexes in aqueous solution were investigated by UV-vis and electron paramagnetic resonance (EPR), and the results were supported by relativistic density functional theory (DFT) calculations. Isomers were detected that differed from their coordination modes. Crystals of [Cu(DO4S)(NO3)]·NO3 and [Cu(DO2A2S)] suitable for X-ray diffraction were obtained. Cyclic voltammetry (CV) experiments highlighted the remarkable stability of the copper complexes with reference to dissociation upon reduction from Cu2+ to Cu+ on the CV time scale. The Cu+ complexes were generated in situ by electrolysis and examined by NMR spectroscopy. DFT calculations gave further structural insights. These results demonstrate that the investigated sulfur-containing chelators are promising candidates for application in copper-based radiopharmaceuticals. In this connection, the high stability of both Cu2+ and Cu+ complexes can represent a key parameter for avoiding in vivo demetalation after bioinduced reduction to Cu+, often observed for other well-known chelators that can stabilize only Cu2+.
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Affiliation(s)
- Marianna Tosato
- Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy
| | - Marco Dalla Tiezza
- Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy
| | - Nóra V May
- Centre for Structural Science, Research Centre for Natural Sciences, Magyar tudósok Körútja 2, 1117 Budapest, Hungary
| | - Abdirisak Ahmed Isse
- Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy
| | - Sonia Nardella
- Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy.,Department of Pharmaceutical Sciences, University of Padova, via Marzolo 8, 35131 Padova, Italy
| | - Laura Orian
- Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy
| | - Marco Verona
- Department of Pharmaceutical Sciences, University of Padova, via Marzolo 8, 35131 Padova, Italy
| | - Christian Vaccarin
- Department of Pharmaceutical Sciences, University of Padova, via Marzolo 8, 35131 Padova, Italy
| | - André Alker
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel F. Hoffmann-La Roche, Grenzacherstrasse 124, 4058 Basel, Switzerland
| | - Helmut Mäcke
- Department of Nuclear Medicine, University Hospital Freiburg, Hugstetterstrasse 55, D-79106 Freiburg, Germany
| | - Paolo Pastore
- Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy
| | - Valerio Di Marco
- Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy
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21
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Klasen B, Moon ES, Rösch F. AAZTA 5-squaramide ester competing with DOTA-, DTPA- and CHX-A″-DTPA-analogues: Promising tool for 177Lu-labeling of monoclonal antibodies under mild conditions. Nucl Med Biol 2021; 96-97:80-93. [PMID: 33839678 DOI: 10.1016/j.nucmedbio.2021.03.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/12/2021] [Accepted: 03/20/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Combining the advantages of both cyclic and acyclic chelator systems, AAZTA (1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine) is well suited for complexation of various diagnostic and therapeutic radiometals such as gallium-68, scandium-44 and lutetium-177 under mild conditions. Due to its specificity for primary amines and pH dependent binding properties, squaric acid (SA) represents an excellent tool for selective coupling of the appropriate chelator to different target vectors. Therefore, the aim of this study was to evaluate radiolabeling properties of the novel bifunctional AAZTA5-SA being coupled to a model antibody (bevacizumab) in comparison to DOTA-SA, DTPA-p-Bn-SA and CHX-A″-DTPA-p-Bn-SA using the therapeutic nuclide lutetium-177. METHODS AND RESULTS As proof-of-concept, bevacizumab was first functionalized with AAZTA5-SA, DOTA-SA, DTPA-p-Bn-SA or CHX-A″-DTPA-p-Bn-SA. After purification via fractionated size exclusion chromatography (SEC), the corresponding immunoconjugates were subsequently radiolabeled with lutetium-177 at pH 7 and room temperature (RT) as well as 37 °C. After 90 min, labeling of AAZTA5-SA-mAb resulted in almost quantitative radiochemical yields (RCY) of >98% and >99%, respectively. Formation of [177Lu]Lu-DTPA-p-Bn-SA-mAb indicated rapid labeling kinetics reaching similar yields at RT already after 30 min. Fast but incomplete radiolabeling of the CHX-A″-analogue could be observed with a yield of 74% after 10 min and no further significant increase. In contrast, 177Lu-labeling of DOTA-SA-mAb showed negligible radiochemical yields of <2% both at room temperature and 37 °C. In vitro complex stability measurements of [177Lu]Lu-AAZTA5-SA-mAb at 37 °C indicated >94% protein bound activity in human serum and >92% in phosphate buffered saline (PBS), respectively within 15 days. [177Lu]Lu-DTPA-p-Bn-SA-mAb and [177Lu]Lu-CHX-A″-DTPA-p-Bn-SA-mAb revealed similar to even slightly higher in vitro stability in both media. CONCLUSION Coupling of AAZTA5-SA to the monoclonal antibody bevacizumab allowed for 177Lu-labeling with almost quantitative radiochemical yields both at room temperature and 37 °C. Within 15 days, the resulting radioconjugate indicated very high in vitro complex stability both in human serum and PBS. Therefore, AAZTA5-SA is a promising tool for 177Lu-labeling of sensitive biomolecules such as antibodies for theranostic applications.
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Affiliation(s)
- Benedikt Klasen
- Department of Chemistry - TRIGA site, Johannes Gutenberg University, Mainz, Germany.
| | - Euy Sung Moon
- Department of Chemistry - TRIGA site, Johannes Gutenberg University, Mainz, Germany.
| | - Frank Rösch
- Department of Chemistry - TRIGA site, Johannes Gutenberg University, Mainz, Germany.
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22
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Choudhary N, Barrett KE, Kubeil M, Radchenko V, Engle JW, Stephan H, de Guadalupe Jaraquemada-Peláez M, Orvig C. Metal ion size profoundly affects H 3glyox chelate chemistry. RSC Adv 2021; 11:15663-15674. [PMID: 35481219 PMCID: PMC9029555 DOI: 10.1039/d1ra01793d] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 04/16/2021] [Indexed: 02/01/2023] Open
Abstract
The bisoxine hexadentate chelating ligand, H3glyox was investigated for its affinity for Mn2+, Cu2+ and Lu3+ ions; all three metal ions are relevant with applications in nuclear medicine and medicinal inorganic chemistry. The aqueous coordination chemistry and thermodynamic stability of all three metal complexes were thoroughly investigated by detailed DFT structure calculations and stability constant determination, by employing UV in-batch spectrophotometric titrations, giving pM values (pM = −log[Mn+]free when [Mn+] = 1 μM, [L] = 10 μM at pH 7.4 and 25 °C) – pCu (25.2) > pLu (18.1) > pMn (12.0). DFT calculated structures revealed different geometries and coordination preferences of the three metal ions; notable was an inner sphere water molecule in the Mn2+ complex. H3glyox labels [52gMn]Mn2+, [64Cu]Cu2+ and [177Lu]Lu3+ at ambient conditions with apparent molar activities of 40 MBq μmol−1, 500 MBq μmol−1 and 25 GBq μmol−1, respectively. Collectively, these initial investigations provide insight into the effects of metal ion size and charge on the chelation with the hexadentate H3glyox and indicate that further investigations of the Mn2+–H3glyox complex in 52g/55Mn-based bimodal imaging might be worthwhile. The bisoxine hexadentate chelating ligand, H3glyox was investigated for its affinity for Mn2+, Cu2+ and Lu3+ ions; all three metal ions are relevant with applications in nuclear medicine and medicinal inorganic chemistry.![]()
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Affiliation(s)
- Neha Choudhary
- Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver British Columbia V6T 1Z1 Canada .,Life Sciences Division, TRIUMF 4004 Wesbrook Mall Vancouver British Columbia V6T 2A3 Canada
| | - Kendall E Barrett
- Department of Medical Physics, University of Wisconsin 1111 Highland Avenue Madison WI 53711 USA
| | - Manja Kubeil
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Bautzner Landstraße 400 D-01328 Dresden Germany
| | - Valery Radchenko
- Life Sciences Division, TRIUMF 4004 Wesbrook Mall Vancouver British Columbia V6T 2A3 Canada.,Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver British Columbia V6T 1Z1 Canada
| | - Jonathan W Engle
- Department of Medical Physics, University of Wisconsin 1111 Highland Avenue Madison WI 53711 USA
| | - Holger Stephan
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Bautzner Landstraße 400 D-01328 Dresden Germany
| | - María de Guadalupe Jaraquemada-Peláez
- Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver British Columbia V6T 1Z1 Canada
| | - Chris Orvig
- Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver British Columbia V6T 1Z1 Canada
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23
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Walke GR, Meron S, Shenberger Y, Gevorkyan‐Airapetov L, Ruthstein S. Cellular Uptake of the ATSM-Cu(II) Complex under Hypoxic Conditions. ChemistryOpen 2021; 10:486-492. [PMID: 33908707 PMCID: PMC8080296 DOI: 10.1002/open.202100044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/08/2021] [Indexed: 12/21/2022] Open
Abstract
The Cu(II)-diacetyl-bis (N4-methylthiosemicarbazone) complex (ATSM-Cu(II)) has been suggested as a promising positron emission tomography (PET) agent for hypoxia imaging. Several in-vivo studies have shown its potential to detect hypoxic tumors. However, its uptake mechanism and its specificity to various cancer cell lines have been less studied. Herein, we tested ATSM-Cu(II) toxicity, uptake, and reduction, using four different cell types: (1) mouse breast cancer cells (DA-3), (2) human embryonic kidney cells (HEK-293), (3) breast cancer cells (MCF-7), and (4) cervical cancer cells (Hela) under normoxic and hypoxic conditions. We showed that ATSM-Cu(II) is toxic to breast cancer cells under normoxic and hypoxic conditions; however, it is not toxic to normal HEK-293 non-cancer cells. We showed that the Cu(I) content in breast cancer cell after treatment with ATSM-Cu(II) under hypoxic conditions is higher than in normal cells, despite that the uptake of ATSM-Cu(II) is a bit higher in normal cells than in breast cancer cells. This study suggests that the redox potential of ATSM-Cu(II) is higher in breast cancer cells than in normal cells; thus, its toxicity to cancer cells is increased.
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Affiliation(s)
- Gulshan R. Walke
- Department of ChemistryFaculty of Exact Sciences, and theInstitute for Nanotechnology and advanced materials (BINA)Bar-Ilan University5290002Ramat-GanIsrael
| | - Shelly Meron
- Department of ChemistryFaculty of Exact Sciences, and theInstitute for Nanotechnology and advanced materials (BINA)Bar-Ilan University5290002Ramat-GanIsrael
| | - Yulia Shenberger
- Department of ChemistryFaculty of Exact Sciences, and theInstitute for Nanotechnology and advanced materials (BINA)Bar-Ilan University5290002Ramat-GanIsrael
| | - Lada Gevorkyan‐Airapetov
- Department of ChemistryFaculty of Exact Sciences, and theInstitute for Nanotechnology and advanced materials (BINA)Bar-Ilan University5290002Ramat-GanIsrael
| | - Sharon Ruthstein
- Department of ChemistryFaculty of Exact Sciences, and theInstitute for Nanotechnology and advanced materials (BINA)Bar-Ilan University5290002Ramat-GanIsrael
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24
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Martin S, Maus S, Stemler T, Rosar F, Khreish F, Holland JP, Ezziddin S, Bartholomä MD. Proof-of-Concept Study of the NOTI Chelating Platform: Preclinical Evaluation of 64Cu-Labeled Mono- and Trimeric c(RGDfK) Conjugates. Mol Imaging Biol 2021; 23:95-108. [PMID: 32856224 PMCID: PMC7782405 DOI: 10.1007/s11307-020-01530-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 07/14/2020] [Accepted: 08/09/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE We recently developed a chelating platform based on the macrocycle 1,4,7-triazacyclononane with up to three five-membered azaheterocyclic arms for the preparation of 68Ga- and 64Cu-based radiopharmaceuticals. Based on this platform, the chelator scaffold NOTI-TVA with three additional carboxylic acid groups for bioconjugation was synthesized and characterized. The primary aims of this proof-of-concept study were (1) to evaluate if trimeric radiotracers on the basis of the NOTI-TVA 6 scaffold can be developed, (2) to determine if the additional substituents for bioconjugation at the non-coordinating NH atoms of the imidazole residues of the building block NOTI influence the metal binding properties, and (3) what influence multiple targeting vectors have on the biological performance of the radiotracer. The cyclic RGDfK peptide that specifically binds to the αvß3 integrin receptor was selected as the biological model system. PROCEDURES Two different synthetic routes for the preparation of NOTI-TVA 6 were explored. Three c(RGDfK) peptide residues were conjugated to the NOTI-TVA 6 building block by standard peptide chemistry providing the trimeric bioconjugate NOTI-TVA-c(RGDfK)3 9. Labeling of 9 with [64Cu]CuCl2 was performed manually at pH 8.2 at ambient temperature. Binding affinities of Cu-8, the Cu2+ complex of the previously described monomer NODIA-Me-c(RGDfK) 8, and the trimer Cu-9 to integrin αvß3 were determined in competitive cell binding experiments in the U-87MG cell line. The pharmacokinetics of both 64Cu-labeled conjugates [64Cu]Cu-8 and [64Cu]Cu-9 were determined by small-animal PET imaging and ex vivo biodistribution studies in mice bearing U-87MG xenografts. RESULTS Depending on the synthetic route, NOTI-TVA 6 was obtained with an overall yield up to 58 %. The bioconjugate 9 was prepared in 41 % yield. Both conjugates [64Cu]Cu-8 and [64Cu]Cu-9 were radiolabeled quantitatively at ambient temperature in high molar activities of Am ~ 20 MBq nmol-1 in less than 5 min. Competitive inhibitory constants IC50 of c(RDGfK) 7, Cu-8, and Cu-9 were determined to be 159.5 ± 1.3 nM, 256.1 ± 2.1 nM, and 99.5 ± 1.1 nM, respectively. In small-animal experiments, both radiotracers specifically delineated αvß3 integrin-positive U-87MG tumors with low uptake in non-target organs and rapid blood clearance. The trimer [64Cu]Cu-9 showed a ~ 2.5-fold higher tumor uptake compared with the monomer [64Cu]Cu-8. CONCLUSIONS Functionalization of NOTI at the non-coordinating NH atoms of the imidazole residues for bioconjugation was straightforward and allowed the preparation of a homotrimeric RGD conjugate. After optimization of the synthesis, required building blocks to make NOTI-TVA 6 are now available on multi-gram scale. Modifications at the imidazole groups had no measurable impact on metal binding properties in vitro and in vivo suggesting that the NOTI scaffold is a promising candidate for the development of 64Cu-labeled multimeric/multifunctional radiotracers.
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Affiliation(s)
- Sebastian Martin
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany
- Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Rue de Bugnon 25A, CH-1011, Lausanne, Switzerland
| | - Stephan Maus
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany
| | - Tobias Stemler
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany
| | - Florian Rosar
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany
| | - Fadi Khreish
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany
| | - Jason P Holland
- Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
| | - Samer Ezziddin
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany
| | - Mark D Bartholomä
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany.
- Department of Nuclear Medicine, University of Freiburg - Medical Center, Hugstetterstrasse 55, 79106, Freiburg, Germany.
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25
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Witney TH, Blower PJ. The chemical tool-kit for molecular imaging with radionuclides in the age of targeted and immune therapy. Cancer Imaging 2021; 21:18. [PMID: 33516256 PMCID: PMC7847158 DOI: 10.1186/s40644-021-00385-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/20/2021] [Indexed: 02/05/2023] Open
Abstract
Nuclear medicine has evolved over the last half-century from a functional imaging modality using a handful of radiopharmaceuticals, many of unknown structure and mechanism of action, into a modern speciality that can properly be described as molecular imaging, with a very large number of specific radioactive probes of known structure that image specific molecular processes. The advances of cancer treatment in recent decades towards targeted and immune therapies, combined with recognition of heterogeneity of cancer cell phenotype among patients, within patients and even within tumours, has created a growing need for personalised molecular imaging to support treatment decision. This article describes the evolution of the present vast range of radioactive probes – radiopharmaceuticals – leveraging a wide variety of chemical disciplines, over the last half century. These radiochemical innovations have been inspired by the need to support personalised medicine and also by the parallel development in development of new radionuclide imaging technologies – from gamma scintigraphy, through single photon emission tomography (SPECT), through the rise of clinical positron emission tomography (PET) and PET-CT, and perhaps in the future, by the advent of total body PET. Thus, in the interdisciplinary world of nuclear medicine and molecular imaging, as quickly as radiochemistry solutions are developed to meet new needs in cancer imaging, new challenges emerge as developments in one contributing technology drive innovations in the others.
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Affiliation(s)
- Timothy H Witney
- School of Biomedical Engineering and Imaging Sciences, King's College London, 4th Floor Lambeth Wing, St Thomas' Hospital, London, SE1 7EH, England
| | - Philip J Blower
- School of Biomedical Engineering and Imaging Sciences, King's College London, 4th Floor Lambeth Wing, St Thomas' Hospital, London, SE1 7EH, England.
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26
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Lee CH, Lim I, Woo SK, Kim KI, Lee KC, Song K, Choi CW, Lim SM. The Feasibility of 64Cu-PSMA I&T PET for Prostate Cancer. Cancer Biother Radiopharm 2021; 37:417-423. [DOI: 10.1089/cbr.2020.4189] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Chul-Hee Lee
- Department of Nuclear Medicine, Korea Cancer Centre Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
- Division of Applied RI, Research Institute of Radiological & Medical Sciences, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
- Department of Urology, Korea Cancer Centre Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Ilhan Lim
- Department of Nuclear Medicine, Korea Cancer Centre Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Sang-Keun Woo
- Department of Nuclear Medicine, Korea Cancer Centre Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
- Department of Nuclear Medicine, Seoul. National University Hospital, Seoul, Republic of Korea
| | - Kwang Il Kim
- Department of Nuclear Medicine, Seoul. National University Hospital, Seoul, Republic of Korea
| | - Kyo Chul Lee
- Department of Nuclear Medicine, Seoul. National University Hospital, Seoul, Republic of Korea
| | - Kanghyon Song
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Chang Woon Choi
- Department of Nuclear Medicine, Korea Cancer Centre Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Sang Moo Lim
- Department of Nuclear Medicine, Korea Cancer Centre Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
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27
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Pan M, Zheng Q, Yu Y, Ai H, Xie Y, Zeng X, Wang C, Liu L, Zhao M. Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative. Nat Commun 2021; 12:121. [PMID: 33402676 PMCID: PMC7785736 DOI: 10.1038/s41467-020-20359-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 11/25/2020] [Indexed: 01/29/2023] Open
Abstract
p97, also known as valosin-containing protein (VCP) or Cdc48, plays a central role in cellular protein homeostasis. Human p97 mutations are associated with several neurodegenerative diseases. Targeting p97 and its cofactors is a strategy for cancer drug development. Despite significant structural insights into the fungal homolog Cdc48, little is known about how human p97 interacts with its cofactors. Recently, the anti-alcohol abuse drug disulfiram was found to target cancer through Npl4, a cofactor of p97, but the molecular mechanism remains elusive. Here, using single-particle cryo-electron microscopy (cryo-EM), we uncovered three Npl4 conformational states in complex with human p97 before ATP hydrolysis. The motion of Npl4 results from its zinc finger motifs interacting with the N domain of p97, which is essential for the unfolding activity of p97. In vitro and cell-based assays showed that the disulfiram derivative bis-(diethyldithiocarbamate)-copper (CuET) can bypass the copper transporter system and inhibit the function of p97 in the cytoplasm by releasing cupric ions under oxidative conditions, which disrupt the zinc finger motifs of Npl4, locking the essential conformational switch of the complex.
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Affiliation(s)
- Man Pan
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, 60637, USA
| | - Qingyun Zheng
- Tsinghua-Peking Center for Life Sciences, Department of Chemistry, Tsinghua University, 100084, Beijing, China
| | - Yuanyuan Yu
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, 60637, USA
| | - Huasong Ai
- Tsinghua-Peking Center for Life Sciences, Department of Chemistry, Tsinghua University, 100084, Beijing, China
| | - Yuan Xie
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, 60637, USA
| | - Xin Zeng
- Peking-Tsinghua Center for Life Sciences, College of Chemistry and Molecular Engineering, Peking University, 100871, Beijing, China
| | - Chu Wang
- Peking-Tsinghua Center for Life Sciences, College of Chemistry and Molecular Engineering, Peking University, 100871, Beijing, China
| | - Lei Liu
- Tsinghua-Peking Center for Life Sciences, Department of Chemistry, Tsinghua University, 100084, Beijing, China.
| | - Minglei Zhao
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, 60637, USA.
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Piccardo A, Ugolini M, Righi S, Bottoni G, Cistaro A, Paparo F, Giovanella L, Evangelista L. Copper, PET/CT and prostate cancer: a systematic review of the literature. THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING : OFFICIAL PUBLICATION OF THE ITALIAN ASSOCIATION OF NUCLEAR MEDICINE (AIMN) [AND] THE INTERNATIONAL ASSOCIATION OF RADIOPHARMACOLOGY (IAR), [AND] SECTION OF THE SOCIETY OF... 2020; 64:382-392. [PMID: 32900177 DOI: 10.23736/s1824-4785.20.03277-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2023]
Abstract
Copper is an essential element that plays an important role in both cancer development and growth. Indeed, high levels of copper have been found in prostate cancer (PCa), and this finding have paved the way for the use of this element as a target for positron emission tomography (PET) imaging. Copper64 (64Cu) can be used alone, as 64CuCl2, and also as a precursor for the in-vitro radio-labelling of specific carriers for PET imaging in PCa, (e.g. associated to prostate-specific membrane antigen: PSMA). The use of 64Cu-PSMA can yield late acquisitions in which PET images are characterized by a higher target-to-background ratio. At the same time, the shorter positron range of 64Cu provides high spatial resolution, which leads to better detection of small lesions. In this context, the aim of this review was to systematically review studies evaluating the identification of PCa in humans by means of 64CuCl2 and other PET tracers radio-labelled with 64Cu.
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Affiliation(s)
- Arnoldo Piccardo
- Department of Nuclear Medicine, EO Ospedali Galliera, Genoa, Italy -
| | - Martina Ugolini
- Department of Nuclear Medicine, EO Ospedali Galliera, Genoa, Italy
| | - Sergio Righi
- Medical Physics Department, EO Ospedali Galliera, Genoa, Italy
| | - Gianluca Bottoni
- Department of Nuclear Medicine, EO Ospedali Galliera, Genoa, Italy
| | - Angelina Cistaro
- Department of Nuclear Medicine, EO Ospedali Galliera, Genoa, Italy
| | | | - Luca Giovanella
- Clinic for Nuclear Medicine, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Laura Evangelista
- Nuclear Medicine Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
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Reactor produced [ 64Cu]CuCl 2 as a PET radiopharmaceutical for cancer imaging: from radiochemistry laboratory to nuclear medicine clinic. Ann Nucl Med 2020; 34:899-910. [PMID: 33048309 DOI: 10.1007/s12149-020-01522-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/07/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Copper-64 is a useful theranostic radioisotope that is attracting renewed interest from the nuclear medicine community in the recent times. This study aims to demonstrate the utility of research reactors to produce clinical-grade 64Cu via 63Cu(n,γ)64Cu reaction and use it in the form of [64Cu]CuCl2 as a radiopharmaceutical for PET imaging of cancer in human patients. METHODS Copper-64 was produced by irradiation of natural CuO target in a medium flux research reactor. The irradiated target was radiochemically processed and detailed quality control analyses were carried out. Sub-acute toxicity studies were carried out with different doses of Cu in Wistar rats. The biological efficacy of the radiopharmaceutical was established in preclinical setting by biodistribution studies in melanoma tumor bearing mice. After getting regulatory approvals, [64Cu]CuCl2 formulation was clinically used for PET imaging of prostate cancer and glioblastoma patients. RESULTS Large-scale (~ 30 GBq) production of 64Cu could be achieved in a typical batch and it was adequate for formulation of clinical doses for multiple patients. The radiopharmaceutical met all the purity requirements for administration in human subjects. Studies carried out in animal model showed that the toxicity due to "cold" Cu in clinical dose of [64Cu]CuCl2 for PET scans would be negligible. Clinical PET scans showed satisfactory uptake of the radiopharmaceutical in the primary cancer and its metastatic sites. CONCLUSIONS To the best of our knowledge, this is the first study on use of reactor produced [64Cu]CuCl2 for PET imaging of cancer in human patients. It is envisaged that this route of production of 64Cu would aid towards affordable availability of this radioisotope for widespread clinical use in countries with limited cyclotron facilities.
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Shin U, Kim J, Lee J, Park D, Lee C, Jung HC, Park J, Lee K, Lee MW, Kim SW, Seo J. Development of 64Cu-loaded Perfluoropentane Nanodroplet: A Potential Tumor Theragnostic Nano-carrier and Dual-Modality PET-Ultrasound Imaging Agents. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:2775-2784. [PMID: 32653208 DOI: 10.1016/j.ultrasmedbio.2020.05.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 04/24/2020] [Accepted: 05/31/2020] [Indexed: 06/11/2023]
Abstract
The purpose of this study was to develop and preliminarily evaluate phospholipid-shelled nanodroplets (NDs) encapsulating perfluoropentane (PFP) and radioactive 64Cu as a hybrid positron emission tomography (PET)-ultrasound (US) probe. PFP NDs were fabricated by mixing liquid-phase PFP with a phospholipid solution. The 64Cu was encapsulated into the NDs in a size-controlled manner by exploiting the hydrophobicity of 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) using a vial mixer and an extruder. The fabricated 64Cu-loaded PFP NDs (64Cu-PFP NDs) were evaluated using in vitro/in vivo PET-computed tomography (PET-CT), US imaging and transmission electron microscopy. In the in vitro PET images, the 64Cu-PFP NDs were observed as a hot spot in the lower section of the test tube. In the acquired US images, the mean region of interest brightness values of 64Cu-PFP NDs were revealed by their strong echo image. In a tumor-bearing mouse animal model, tumor uptake of the 64Cu-PFP NDs was low, that is, approximately 65%, compared with that of only free 64Cu, as determined by PET-delayed imaging analysis. The dual-function concept of the NDs is expected to contribute to the prognosis and effectiveness of therapy by fusing the science and technology of nuclear medicine and US.
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Affiliation(s)
- Unchol Shin
- Department of Biomedical Engineering, College of Health Sciences, Yonsei University, Seoul, Republic of Korea; College of Health Sciences, Institute of Health Science, Korea University, Seoul, Republic of Korea
| | - Jungyoung Kim
- Department of Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Jiwoong Lee
- College of Health Sciences, Institute of Health Science, Korea University, Seoul, Republic of Korea
| | - Donghee Park
- Bioinfra Inc., Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Changmoon Lee
- Department of Biomedical Engineering, College of Engineering, Chonnam National University, Gwangju, Republic of Korea
| | - Hyon Chel Jung
- College of Health Sciences, Institute of Health Science, Korea University, Seoul, Republic of Korea
| | - Jiae Park
- Department of Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Kyochul Lee
- Department of Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Min Woo Lee
- College of Health Sciences, Institute of Health Science, Korea University, Seoul, Republic of Korea
| | - Suhng Wook Kim
- College of Health Sciences, Institute of Health Science, Korea University, Seoul, Republic of Korea
| | - Jongbum Seo
- Department of Biomedical Engineering, College of Health Sciences, Yonsei University, Seoul, Republic of Korea.
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PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction. Antioxidants (Basel) 2020; 9:antiox9090861. [PMID: 32937849 PMCID: PMC7554831 DOI: 10.3390/antiox9090861] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/11/2020] [Accepted: 09/12/2020] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress based on mitochondrial dysfunction is assumed to be the principal molecular mechanism for the pathogenesis of many neurodegenerative disorders. However, the effects of oxidative stress on the neurodegeneration process in living patients remain to be elucidated. Molecular imaging with positron emission tomography (PET) can directly evaluate subtle biological changes, including the redox status. The present review focuses on recent advances in PET imaging for oxidative stress, in particular the use of the Cu-ATSM radioligand, in neurodegenerative disorders associated with mitochondrial dysfunction. Since reactive oxygen species are mostly generated by leakage of excess electrons from an over-reductive state due to mitochondrial respiratory chain impairment, PET with 62Cu-ATSM, the accumulation of which depends on an over-reductive state, is able to image oxidative stress. 62Cu-ATSM PET studies demonstrated enhanced oxidative stress in the disease-related brain regions of patients with mitochondrial disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, the magnitude of oxidative stress increased with disease severity, indicating that oxidative stress based on mitochondrial dysfunction contributes to promoting neurodegeneration in these diseases. Oxidative stress imaging has improved our insights into the pathological mechanisms of neurodegenerative disorders, and is a promising tool for monitoring further antioxidant therapies.
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Kaur A, New EJ, Sunde M. Strategies for the Molecular Imaging of Amyloid and the Value of a Multimodal Approach. ACS Sens 2020; 5:2268-2282. [PMID: 32627533 DOI: 10.1021/acssensors.0c01101] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Protein aggregation has been widely implicated in neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and Huntington disease, as well as in systemic amyloidoses and conditions associated with localized amyloid deposits, such as type-II diabetes. The pressing need for a better understanding of the factors governing protein assembly has driven research for the development of molecular sensors for amyloidogenic proteins. To date, a number of sensors have been developed that report on the presence of protein aggregates utilizing various modalities, and their utility demonstrated for imaging protein aggregation in vitro and in vivo. Analysis of these sensors highlights the various advantages and disadvantages of the different imaging modalities and makes clear that multimodal sensors with properties amenable to more than one imaging technique need to be developed. This critical review highlights the key molecular scaffolds reported for molecular imaging modalities such as fluorescence, positron emission tomography, single photon emission computed tomography, and magnetic resonance imaging and includes discussion of the advantages and disadvantages of each modality, and future directions for the design of amyloid sensors. We also discuss the recent efforts focused on the design and development of multimodal sensors and the value of cross-validation across multiple modalities.
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Affiliation(s)
- Amandeep Kaur
- The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, Sydney, New South Wales 2006, Australia
- The University of Sydney, Nano Institute (Sydney Nano), The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Elizabeth J. New
- The University of Sydney, Nano Institute (Sydney Nano), The University of Sydney, Sydney, New South Wales 2006, Australia
- The University of Sydney, School of Chemistry, Faculty of Science, Sydney, New South Wales 2006, Australia
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Margaret Sunde
- The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, Sydney, New South Wales 2006, Australia
- The University of Sydney, Nano Institute (Sydney Nano), The University of Sydney, Sydney, New South Wales 2006, Australia
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Chakravarty R, Rajeswari A, Shetty P, Jagadeesan KC, Ram R, Jadhav S, Sarma HD, Dash A, Chakraborty S. A simple and robust method for radiochemical separation of no-carrier-added 64Cu produced in a research reactor for radiopharmaceutical preparation. Appl Radiat Isot 2020; 165:109341. [PMID: 32745917 DOI: 10.1016/j.apradiso.2020.109341] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/29/2020] [Accepted: 07/13/2020] [Indexed: 12/25/2022]
Abstract
Copper-64 is an excellent theranostic radiometal that is gaining renewed attention of the clinical community in the recent times. In order to meet the increasing demand of this radiometal, we have demonstrated the viability of its production via 64Zn (n,p) 64Cu reaction in a nuclear reactor. A semi-automated radiochemical separation module based on selective extraction of 64Cu as dithizonate complex was developed. The maximum available activity at the end of irradiation was ~ 700 MBq. The overall yield of 64Cu after the separation process was >85% and it could be obtained with ~12 GBq/μg specific activity, >99.9% radionuclidic purity and >98% radiochemical purity. The separated 64Cu could be utilized for preparation of a wide variety of radiopharmaceuticals.
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Affiliation(s)
- Rubel Chakravarty
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400094, India.
| | - Ardhi Rajeswari
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India
| | - Priyalata Shetty
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India
| | - K C Jagadeesan
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India
| | - Ramu Ram
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India
| | - Sachin Jadhav
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India
| | - Haladhar Dev Sarma
- Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India
| | - Ashutosh Dash
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400094, India
| | - Sudipta Chakraborty
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400094, India.
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Preclinical PET imaging study of lung cancer with 64CuCl 2. Ann Nucl Med 2020; 34:653-662. [PMID: 32567008 DOI: 10.1007/s12149-020-01491-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/15/2020] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Human copper transporter 1 (CTR1) has been proven to be overexpressed in many types of cancer cells, and copper (II)-64 chloride (64CuCl2) has been used as an effective tracer for positron emission tomography (PET) imaging in tumor-bearing animal models. Thus, this study aimed to investigate the potential application of 64CuCl2 in PET imaging of lung cancer through targeting CTR1. METHODS The expression of CTR1 in a series of lung cancer cell lines was identified by quantitative real-time polymerase chain reaction (Q-PCR), western blot, enzyme-linked immunosorbnent assay (ELISA), and immunofluorescent staining. Then in vitro cell uptake assay of 64CuCl2 was investigated in human lung cancer cell lines with different levels of CTR1 expression. Small animal PET imaging and quantitative analysis were performed in human lung cancer tumor-bearing mice after intravenous injection of 64CuCl2, respectively. RESULTS The CTR1 expression in multiple human lung cancer cells was identified and confirmed, and H1299 cell lines with high CTR1 expression, H460 with moderate CTR1, and H1703 with low CTR1 were selected for further experiments. In vitro cellular uptake assay displayed that the 64CuCl2 uptake by these three kinds of cells was positively correlated with their CTR1 expressed levels. The blocking experiments testified the specificity of 64CuCl2 to target CTR1. Moreover, small animal PET imaging and quantitative results showed that 64CuCl2 accumulation in H1299, H460, and H1703 tumor-bearing mice were consistent with CTR1 levels and cell uptake experiments. CONCLUSIONS The expression of CTR1 in human lung cancer xenograft model could be successfully visualized by 64CuCl2 PET examination. With the expected growth of PET/CT examination to be an essential strategy in clinical lung cancer management, 64CuCl2 has the potential to be a promising PET imaging agent of lung cancer.
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35
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Qi S, Hoppmann S, Xu Y, Cheng Z. PET Imaging of HER2-Positive Tumors with Cu-64-Labeled Affibody Molecules. Mol Imaging Biol 2020; 21:907-916. [PMID: 30617730 DOI: 10.1007/s11307-018-01310-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
PURPOSE Previous studies has demonstrated the utility of human epidermal growth factor receptor type 2 (HER2) as an attractive target for cancer molecular imaging and therapy. An affibody protein with strong binding affinity for HER2, ZHER2:342, has been reported. Various methods of chelator conjugation for radiolabeling HER2 affibody molecules have been described in the literature including N-terminal conjugation, C-terminal conjugation, and other methods. Cu-64 has recently been extensively evaluated due to its half-life, decay properties, and availability. Our goal was to optimize the radiolabeling method of this affibody molecule with Cu-64, and translate a positron emission tomography (PET) probe with the best in vivo performance to clinical PET imaging of HER2-positive cancers. PROCEDURES In our study, three anti-HER2 affibody proteins-based PET probes were prepared, and their in vivo performance was evaluated in mice bearing HER2-positive subcutaneous SKOV3 tumors. The affibody analogues, Ac-Cys-ZHER2:342, Ac-ZHER2:342(Cys39), and Ac-ZHER2:342-Cys, were synthesized using the solid phase peptide synthesis method. The purified small proteins were site-specifically conjugated with the maleimide-functionalized chelator, 1,4,7,10-tetraazacyclododecane-1,4,7-tris- aceticacid-10-maleimidethylacetamide (maleimido-mono-amide-DOTA). The resulting DOTA-affibody conjugates were then radiolabeled with Cu-64. Cell uptake assay of the resulting PET probes, [64Cu]DOTA-Cys-ZHER2:342, [64Cu]DOTA-ZHER2:342(Cys39), and [64Cu]DOTA-ZHER2:342-Cys, was performed in HER2-positive human ovarian SKOV3 carcinoma cells at 4 and 37 °C. The binding affinities of the radiolabeled peptides were tested by cell saturation assay using SKOV3 cells. PET imaging, biodistribution, and metabolic stability studies were performed in mice bearing SKOV3 tumors. RESULTS Cell uptake assays showed high and specific uptake by incubation of Cu-64-labeled affibodies with SKOV3 cells. The affinities (KD) of the PET radio probes as tested by cell saturation analysis were in the low nanomolar range with the ranking of [64Cu]DOTA-Cys-ZHER2:342 (25.2 ± 9.2 nM) ≈ [64Cu]DOTA-ZHER2:342-Cys (32.6 ± 14.7 nM) > [64Cu]DOTA-ZHER2:342(Cys39) (77.6 ± 22.2 nM). In vitro stability and in vivo metabolite analysis study revealed that all three probes were stable enough for in vivo imaging applications, while [64Cu]DOTA-Cys-ZHER2:342 showed the highest stability. In vivo small-animal PET further demonstrated fast tumor targeting, good tumor accumulation, and good tumor to normal tissue contrast of all three probes. For [64Cu]DOTA-Cys-ZHER2:342, [64Cu]DOTA-ZHER2:342(Cys39), and [64Cu]DOTA-ZHER2:342-Cys, tumor uptake at 24 h are 4.0 ± 1.0 % ID/g, 4.0 ± 0.8 %ID/g, and 4.3 ± 0.7 %ID/g, respectively (mean ± SD, n = 4). Co-injection of the probes with non-labeled anti-HER2 affibody proteins confirmed in vivo specificities of the compounds by tumor uptake reduction. CONCLUSIONS The three Cu-64-labeled ZHER2:342 analogues all display excellent HER2 targeting ability and tumor PET imaging quality. Although varied in the position of the radiometal labeling of these three Cu-64-labeled ZHER2:342 analogues, there is no significant difference in tumor and normal tissue uptakes among the three probes. [64Cu]DOTA-Cys-ZHER2:342 stands out as the most superior PET probe because of its highest affinities and in vivo stability.
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Affiliation(s)
- Shibo Qi
- School of Environmental and Chemical Engineering, Tianjin Polytechnic University, Tianjin, 300387, China.,Molecular Imaging Program at Stanford (MIPS), Department of Radiology, and Bio-X Program, Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, CA, 94305-5344, USA
| | - Susan Hoppmann
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, and Bio-X Program, Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, CA, 94305-5344, USA
| | - Yingding Xu
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, and Bio-X Program, Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, CA, 94305-5344, USA
| | - Zhen Cheng
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, and Bio-X Program, Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, CA, 94305-5344, USA.
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Aleshin GY, Egorova BV, Priselkova AB, Zamurueva LS, Khabirova SY, Zubenko AD, Karnoukhova VA, Fedorova OA, Kalmykov SN. Zinc and copper complexes with azacrown ethers and their comparative stability in vitro and in vivo. Dalton Trans 2020; 49:6249-6258. [PMID: 32329503 DOI: 10.1039/d0dt00645a] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Copper-based radiopharmaceuticals are of high interest these days owing to the decay properties of copper radioisotopes. In contrast, labeled zinc compounds have been less studied for applications in nuclear medicine. In this study, the stability of labeled zinc and copper complexes with two azacrown ether ligands was investigated and compared. Then, the in vitro and in vivo stability of the studied zinc complexes was demonstrated, with the complexes showing promise for biomedical applications. In contrast, analogous copper complexes quickly dissociated in the presence of serum proteins. Furthermore, a simple method for the production of radiochemically pure 65Zn was proposed, and the opportunity for its use as a surrogate radionuclide for research into potential zinc-containing radiopharmaceuticals was demonstrated.
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Affiliation(s)
- Gleb Yu Aleshin
- Lomonosov Moscow State University, 119991 Leninskie Gory, 1/3, Moscow, Russian Federation.
| | - Bayirta V Egorova
- Lomonosov Moscow State University, 119991 Leninskie Gory, 1/3, Moscow, Russian Federation.
| | - Anna B Priselkova
- Lomonosov Moscow State University, 119991 Leninskie Gory, 1/3, Moscow, Russian Federation.
| | - Lyubov S Zamurueva
- Lomonosov Moscow State University, 119991 Leninskie Gory, 1/3, Moscow, Russian Federation.
| | - Sofia Yu Khabirova
- Lomonosov Moscow State University, 119991 Leninskie Gory, 1/3, Moscow, Russian Federation.
| | - Anastasia D Zubenko
- A. N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, 119991 Vavilova, 28, GSP-1, Moscow, Russian Federation
| | - Valentina A Karnoukhova
- A. N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, 119991 Vavilova, 28, GSP-1, Moscow, Russian Federation
| | - Olga A Fedorova
- A. N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, 119991 Vavilova, 28, GSP-1, Moscow, Russian Federation
| | - Stepan N Kalmykov
- Lomonosov Moscow State University, 119991 Leninskie Gory, 1/3, Moscow, Russian Federation. and National Research Center "Kurchatov Institute", 123098 Akademika Kurchatova sqr., 1, Moscow, Russian Federation
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Cullinane C, Jeffery CM, Roselt PD, van Dam EM, Jackson S, Kuan K, Jackson P, Binns D, van Zuylekom J, Harris MJ, Hicks RJ, Donnelly PS. Peptide Receptor Radionuclide Therapy with 67Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model. J Nucl Med 2020; 61:1800-1805. [PMID: 32414949 DOI: 10.2967/jnumed.120.243543] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 04/16/2020] [Indexed: 01/13/2023] Open
Abstract
Peptide receptor radionuclide therapy (PRRT) using radiolabeled octreotate is an effective treatment for somatostatin receptor 2-expressing neuroendocrine tumors. The diagnostic and therapeutic potential of 64Cu and 67Cu, respectively, offers the possibility of using a single somatostatin receptor-targeted peptide conjugate as a theranostic agent. A sarcophagine cage amine ligand, MeCOSar (5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid), conjugated to (Tyr3)-octreotate, called 64Cu-CuSarTATE, was demonstrated to be an imaging agent and potential prospective dosimetry tool in 10 patients with neuroendocrine tumors. This study aimed to explore the antitumor efficacy of 67Cu-CuSarTATE in a preclinical model of neuroendocrine tumors and compare it with the standard PRRT agent, 177Lu-LuDOTA-Tyr3-octreotate (177Lu-LuTATE). Methods: The antitumor efficacy of various doses of 67Cu-CuSarTATE in AR42J (rat pancreatic exocrine) tumor-bearing mice was compared with 177Lu-LuTATE. Results: Seven days after a single administration of 67Cu-CuSarTATE (5 MBq), tumor growth was inhibited by 75% compared with vehicle control. Administration of 177Lu-LuTATE (5 MBq) inhibited tumor growth by 89%. Survival was extended from 12 d in the control group to 21 d after treatment with both 67Cu-CuSarTATE and 177Lu-LuTATE. In a second study, the efficacy of fractionated delivery of PRRT was assessed, comparing the efficacy of 30 MBq of 67Cu-CuSarTATE or 177Lu-LuTATE, either as a single intravenous injection or as two 15-MBq fractions 2 wk apart. Treatment of tumors with 2 fractions significantly improved survival over delivery as a single fraction (67Cu-CuSarTATE: 47 vs. 36 d [P = 0.036]; 177Lu-LuTATE: 46 vs. 29 d [P = 0.040]). Conclusion: This study demonstrates that 67Cu-CuSarTATE is well tolerated in BALB/c nude mice and highly efficacious against AR42J tumors in vivo. Administration of 67Cu-CuSarTATE and 177Lu-LuTATE divided into 2 fractions over 2 wk was more efficacious than administration of a single fraction. The antitumor activity of 67Cu-CuSarTATE in the AR42J tumor model demonstrated the suitability of this novel agent for clinical assessment in the treatment of somatostatin receptor 2-expressing neuroendocrine tumors.
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Affiliation(s)
- Carleen Cullinane
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | | | - Peter D Roselt
- Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Ellen M van Dam
- Clarity Pharmaceuticals Ltd., Eveleigh, New South Wales, Australia
| | - Susan Jackson
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Kevin Kuan
- Molecular Imaging and Therapy Research Unit, SAHMRI, Adelaide, South Australia, Australia; and
| | - Price Jackson
- Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - David Binns
- Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Jessica van Zuylekom
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Matthew J Harris
- Clarity Pharmaceuticals Ltd., Eveleigh, New South Wales, Australia
| | - Rodney J Hicks
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Paul S Donnelly
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia
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38
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Fan D, Wang K, Gao H, Luo Q, Wang X, Li X, Tong W, Zhang X, Luo C, Yang G, Ai L, Shi J. A 64 Cu-porphyrin-based dual-modal molecular probe with integrin α v β 3 targeting function for tumour imaging. J Labelled Comp Radiopharm 2020; 63:212-221. [PMID: 32083750 DOI: 10.1002/jlcr.3833] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 02/17/2020] [Accepted: 02/19/2020] [Indexed: 02/01/2023]
Abstract
Pyropheophorbide-a (Pyro) is a promising multifunctional molecule for multimodal tumour imaging and photodynamic therapy, but its clinical applications are seriously restricted by the limited tumour accumulation capability. Here, we designed and synthesized a small-molecule probe that achieved specific dual-modal tumour imaging based on Pyro. Briefly, a novel molecule combining Pyro, an RGD dimer peptide (3PRGD2 ) and 64 Cu, was designed and synthesized, and the obtained molecule, 64 Cu-Pyro-3PRGD2 , exhibited high tumour specificity in both positron emission tomography and optical imaging in vivo. c (RGDfk) peptide blocking significantly reduced the efficacy of the probe, which confirmed the integrin αV β3 targeting of this molecular probe. 64 Cu-Pyro-3PRGD2 had very low accumulation in normal organs and could be rapidly cleared through kidney metabolism, which prevented the potential damage to adjacent normal tissues. Overall, combining tumour targeting, dual-modal imaging, and biosafety, 64 Cu-Pyro-3PRGD2 has the potential for clinical use as a molecular imaging probe for tumour diagnosis.
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Affiliation(s)
- Di Fan
- Department of Nuclear Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Kai Wang
- Department of Nuclear Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Hannan Gao
- Medical Isotopes Research Center, Peking University, Beijing, China
| | - Qi Luo
- Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing, China
| | - Xin Wang
- Department of Nuclear Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xiaotong Li
- Department of Nuclear Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wu Tong
- Department of Nuclear Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xin Zhang
- Medical Isotopes Research Center, Peking University, Beijing, China
| | - Chuangwei Luo
- Medical Isotopes Research Center, Peking University, Beijing, China
| | - Guangjie Yang
- Medical Isotopes Research Center, Peking University, Beijing, China
| | - Lin Ai
- Department of Nuclear Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Jiyun Shi
- Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing, China
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Radiolabeled Cationic Peptides for Targeted Imaging of Infection. CONTRAST MEDIA & MOLECULAR IMAGING 2020; 2019:3149249. [PMID: 32063807 PMCID: PMC7008241 DOI: 10.1155/2019/3149249] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 05/20/2019] [Accepted: 06/16/2019] [Indexed: 11/18/2022]
Abstract
Molecular probes targeting bacteria provide opportunities to target bacterial infections in vivo for both imaging and therapy. In the current study, we report the development of positron emission tomography (PET) probes for imaging of live bacterial infection based on the small molecules HLys-DOTA, a polycationic peptide synthesized as the D-isomer (RYWVAWRNRG) conjugated to 1, 4, 7, 10-tetraazacyclododecane-N',N″,N‴,N-tetraacetic acid (DOTA) and AB1-HLys-DOTA, which includes an unnatural amino acid AB1 that preferentially binds to bacteria membrane lipids with amine groups via formation of iminoboronates. HLys-DOTA and AB1-HLys-DOTA peptides were radiolabeled with 64Cu and investigated as PET imaging agents to track bacterial infection in vitro and in intramuscularly infected (IM) mice models. Cell uptake studies at 37°C in Staphylococcus aureus (SA) show higher uptake of 64Cu-AB1-HLys-DOTA; 98.47 ± 3.54% vs 64Cu-HLys-DOTA; 39.12 ± 3.27% at 24 h. Standard uptake values (SUV) analysis of the PET images resulted in mean SUV of 0.70 ± 0.08, 0.49 ± 0.04, and 0.31 ± 0.01 for 64Cu-AB1-HLys-DOTA and 0.17 ± 0.06, 0.16 ± 0.02, and 0.13 ± 0.01 for 64Cu-HLys-DOTA at 1, 4, and 24 h post injection, respectively, in the infected muscles. Similarly, in the biodistribution studies, dose uptake in the infected muscles was 4 times higher in the targeted 64Cu-AB1-HLys-DOTA group than in the 64Cu-HLys-DOTA group and 2-3 times higher than in the PBS control group at 1, 4, and 24 h post injection. 64Cu-AB1-HLys-DOTA was able to distinguish between SA-infected muscle and Pseudomonas aeruginosa (PA) infected muscle with lower mean SUV of 0.28 ± 0.10 at 1 h post injection. This illustrates the utility of the AB1 covalently targeting group in synergy with the HLys peptide, which noncovalently binds to bacterial membranes. These results suggest that 64Cu-labeled AB1-HLys-DOTA peptide could be used as an imaging probe for detection of bacterial infection in vivo with specificity for Gram-positive bacteria.
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do Carmo SJC, Scott PJH, Alves F. Production of radiometals in liquid targets. EJNMMI Radiopharm Chem 2020; 5:2. [PMID: 31925619 PMCID: PMC6954154 DOI: 10.1186/s41181-019-0088-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 12/23/2019] [Indexed: 12/27/2022] Open
Abstract
Over the last several years, the use of radiometals has gained increasing relevance in supporting the continuous development of new, complementary and more specific biological targeting agents. Radiopharmaceuticals labelled with radiometals from elements such as Tc, Zr, Y, Ga and Cu received increasing attention as they find application in both diagnostic SPECT and PET imaging techniques and radiotherapeutic purposes. Such interest stems from the wide variety of radionuclides available with distinct and complementary nuclear decay characteristics to choose from with unequalled specificity, but can also be explained by growing demand in targeted radionuclide therapy. As a result, as routine supply of these radiometals becomes mandatory, studies describing their production processes have expanded rapidly. Although most radiometals are traditionally provided by the irradiation of solid targets in specialized cyclotrons, recently developed techniques for producing radiometals through the irradiation of liquid targets have received growing attention due to compatibility with commonly available small medical cyclotrons, promising characteristics and encouraging results. Irradiating liquid targets to produce radiometals appears as a fast, reliable, convenient and cost-efficient alternative to the conventional solid target techniques, characterized by complex and time-consuming pre- and post-irradiation target handling. Production of radiometals in liquid targets incorporated to complete manufacturing processes for daily routine is already recognized as a viable alternative and complementary supply methodology to existing solid target based infrastructures to satisfy growing clinical demands. For instance, several sites already use the approach to produce 68Ga-radiopharmaceuticals for clinical use. This review article covers the production of common radiometals with clinical potential through the irradiation liquid targets. A comparison with the traditional solid target irradiation methods is presented when relevant.
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Affiliation(s)
- Sergio J C do Carmo
- ICNAS - Produção, Pólo das Ciências da Saúde, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal
| | - Peter J H Scott
- Department of Radiology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Francisco Alves
- ICNAS - Institute for Nuclear Sciences Applied to Health, Pólo das Ciências da Saúde, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal. .,IPC - Instituto Politécnico de Coimbra, Coimbra Health School, 3046-854, Coimbra, Portugal.
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Sitarz M, Cussonneau JP, Matulewicz T, Haddad F. Radionuclide candidates for β+γ coincidence PET: An overview. Appl Radiat Isot 2020; 155:108898. [DOI: 10.1016/j.apradiso.2019.108898] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 09/11/2019] [Accepted: 09/19/2019] [Indexed: 12/20/2022]
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Ohya T, Nagatsu K, Hanyu M, Minegishi K, Zhang MR. Simple separation of 67Cu from bulk zinc by coprecipitation using hydrogen sulfide gas and silver nitrate. RADIOCHIM ACTA 2019. [DOI: 10.1515/ract-2019-3168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Abstract
Copper-67 (67Cu), a feasible radionuclide for diagnosis and radiotherapy, is commercially generated from a bulk zinc (Zn) target using the 68Zn(p, 2p)67Cu and 68Zn(γ, p)67Cu nuclear reactions. Because it uses a large amount of zinc, the separation is complex – requiring a combination of three ion exchange columns – and is time-consuming (about 1 day). We developed a quick and easy separation method referred to as “double coprecipitation” using H2S gas and silver nitrate as coprecipitation agents in place of ion exchange columns. We compared this method with a conventional separation method using three ion exchange columns (AG50W-X8, AG1-X8, and Chelex-100) for a natural zinc (natZn) target irradiated by a proton beam. The product quality and the recovery rate with the new method were competitive with the conventional method, and the total operation time was reduced from 1 day to <3 h.
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Affiliation(s)
- Tomoyuki Ohya
- Department of Radiopharmaceuticals Development , National Institutes for Quantum and Radiological Science and Technology (NIRS-QST) , 4-9-1 Anagawa, Inage-ku , Chiba 263-8555 , Japan
| | - Kotaro Nagatsu
- National Institutes for Quantum and Radiological Science and Technology (NIRS-QST) , 4-9-1 Anagawa, Inage-ku , Chiba 263-8555 , Japan
| | - Masayuki Hanyu
- National Institutes for Quantum and Radiological Science and Technology (NIRS-QST) , 4-9-1 Anagawa, Inage-ku , Chiba 263-8555 , Japan
| | - Katsuyuki Minegishi
- National Institutes for Quantum and Radiological Science and Technology (NIRS-QST) , 4-9-1 Anagawa, Inage-ku , Chiba 263-8555 , Japan
| | - Ming-Rong Zhang
- National Institutes for Quantum and Radiological Science and Technology (NIRS-QST) , 4-9-1 Anagawa, Inage-ku , Chiba 263-8555 , Japan
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MacPherson DS, Fung K, Cook BE, Francesconi LC, Zeglis BM. A brief overview of metal complexes as nuclear imaging agents. Dalton Trans 2019; 48:14547-14565. [PMID: 31556418 PMCID: PMC6829947 DOI: 10.1039/c9dt03039e] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Metallic radionuclides have been instrumental in the field of nuclear imaging for over half a century. While recent years have played witness to a dramatic rise in the use of radiometals as labels for chelator-bearing biomolecules, imaging agents based solely on coordination compounds of radiometals have long played a critical role in the discipline as well. In this work, we seek to provide a brief overview of metal complex-based radiopharmaceuticals for positron emission tomography (PET) and single photon emission computed tomography (SPECT). More specifically, we have focused on imaging agents in which the metal complex itself rather than a pendant biomolecule or targeting moiety is responsible for the in vivo behavior of the tracer. This family of compounds contains metal complexes based on an array of different nuclides as well as probes that have been used for the imaging of a variety of pathologies, including infection, inflammation, cancer, and heart disease. Indeed, two of the defining traits of transition metal complexes-modularity and redox chemistry-have both been creatively leveraged in the development of imaging agents. In light of our audience, particular attention is paid to structure and mechanism, though clinical data is addressed as well. Ultimately, it is our hope that this review will not only educate readers about some of the seminal work performed in this space over the last 30 years but also spur renewed interest in the creation of radiopharmaceuticals based on small metal complexes.
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Affiliation(s)
- Douglas S MacPherson
- Department of Chemistry, Hunter College of the City University of New York, New York, NY 10028, USA.
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Carlos Dos Santos J, Beijer B, Bauder-Wüst U, Schäfer M, Leotta K, Eder M, Benešová M, Kleist C, Giesel F, Kratochwil C, Kopka K, Haberkorn U, Mier W. Development of Novel PSMA Ligands for Imaging and Therapy with Copper Isotopes. J Nucl Med 2019; 61:70-79. [PMID: 31541034 DOI: 10.2967/jnumed.119.229054] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 06/12/2019] [Indexed: 01/05/2023] Open
Abstract
Prostate-specific membrane antigen (PSMA)-binding tracers have been shown to be promising agents for the specific targeting of prostate tumors. On labeling with the short-lived isotopes 18F and 68Ga, excellent molecular imaging performance is achieved. This potential could be further exploited using long-lived isotopes. Because of the favorable half-life of 64Cu, tracers labeled with this PET nuclide could solve logistic problems. Moreover, this isotope provides a theranostic pair with the therapeutic copper isotope 67Cu. Hence, 9 novel tracers that combine dedicated copper chelators with the PSMA-specific urea-based binding motif were developed. Methods: The precursors were obtained by solid-phase synthesis. The purity and molecular weight of the PSMA ligands were confirmed by high-performance liquid chromatography and liquid chromatography-mass spectrometry. The compounds were labeled with 64Cu, with a radiolabeling yield of more than 99%. Competitive cell binding assays and internalization assays were performed with C4-2 cells, a subline of the PSMA-positive cell line LNCaP (human lymph node carcinoma of the prostate). In vitro serum stability, the stability of 64Cu-CA003 in blood, and the in vivo fate of neat 64Cu-chloride or 64Cu-CA003 were determined to prove whether the stability of the radiolabeled compounds is sufficient to ensure no significant loss of copper during the targeting process. For PET imaging and biodistribution studies, a C4-2 tumor-bearing mouse model was used. Results: The radiolabeled 64Cu-PSMA ligands showed high serum stability. All PSMA ligands showed high inhibition potencies, with equilibrium inhibition constants in the low nanomolar range. 64Cu-CA003 and 64Cu-CA005 showed high internalization ratios (34.6% ± 2.8 and 18.6% ± 4.4, respectively). Both the in vitro serum stability determination and the in vivo characterization of the main radiolabeled compounds confirmed that, except for 64Cu-PSMA-617, all compounds showed high serum stability within the observation period of 24 h. Small-animal PET imaging demonstrated high tumor uptake within 20 min. Organ distribution studies confirmed high specific uptake in the tumor, with 30.8 ± 12.6 percentage injected dose (%ID)/g at 1 h after injection. Rapid clearance from the kidneys was observed-a decrease from 67.0 ± 20.9 %ID/g at 1 h after injection to 7.5 ± 8.51 %ID/g at 24 h after injection (in the case of CA003). The performance of CA003, the compound with the best preclinical properties, was assessed in a first patient. In line with its preclinical data, PET imaging resulted in clear visualization of the cancer lesions, with high contrast. Conclusion: The 64Cu-labeled PSMA ligands are promising agents to target PSMA and visualize PSMA-positive tumor lesions as shown in preclinical evaluation by small-animal PET studies, organ distribution, and a patient application. Most importantly, the images obtained at 20 h enabled delineation of unclear lesions, showing that the compounds fulfill the prerequisite for dosimetry in the course of therapy planning with 67Cu. Thus, we suggest clinical use of copper-labeled CA003 for diagnostics and radiotherapy of prostate cancer.
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Affiliation(s)
| | - Barbro Beijer
- Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
| | - Ulrike Bauder-Wüst
- Division of Radiopharmaceutical Chemistry, German Cancer Research Center, Heidelberg, Germany
| | - Martin Schäfer
- Division of Radiopharmaceutical Chemistry, German Cancer Research Center, Heidelberg, Germany
| | - Karin Leotta
- Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
| | - Matthias Eder
- Division of Radiopharmaceutical Development, German Cancer Consortium Freiburg, Department of Nuclear Medicine, University of Freiburg, Freiburg, Germany; and
| | - Martina Benešová
- Division of Radiopharmaceutical Chemistry, German Cancer Research Center, Heidelberg, Germany
| | - Christian Kleist
- Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
| | - Frederik Giesel
- Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
| | - Clemens Kratochwil
- Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
| | - Klaus Kopka
- Division of Radiopharmaceutical Chemistry, German Cancer Research Center, Heidelberg, Germany
| | - Uwe Haberkorn
- Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.,Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany
| | - Walter Mier
- Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
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van der Meulen NP, Hasler R, Blanc A, Farkas R, Benešová M, Talip Z, Müller C, Schibli R. Implementation of a new separation method to produce qualitatively improved 64
Cu. J Labelled Comp Radiopharm 2019; 62:460-470. [DOI: 10.1002/jlcr.3730] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 03/06/2019] [Accepted: 03/20/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Nicholas P. van der Meulen
- Laboratory of Radiochemistry; Paul Scherrer Institute; Villigen-PSI Switzerland
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ; Paul Scherrer Institute; Villigen-PSI Switzerland
| | - Roger Hasler
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ; Paul Scherrer Institute; Villigen-PSI Switzerland
| | - Alain Blanc
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ; Paul Scherrer Institute; Villigen-PSI Switzerland
| | - Renata Farkas
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ; Paul Scherrer Institute; Villigen-PSI Switzerland
| | - Martina Benešová
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ; Paul Scherrer Institute; Villigen-PSI Switzerland
- Department of Chemistry and Applied Biosciences; ETH Zurich; Zurich Switzerland
| | - Zeynep Talip
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ; Paul Scherrer Institute; Villigen-PSI Switzerland
| | - Cristina Müller
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ; Paul Scherrer Institute; Villigen-PSI Switzerland
- Department of Chemistry and Applied Biosciences; ETH Zurich; Zurich Switzerland
| | - Roger Schibli
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ; Paul Scherrer Institute; Villigen-PSI Switzerland
- Department of Chemistry and Applied Biosciences; ETH Zurich; Zurich Switzerland
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Ohya T, Minegishi K, Suzuki H, Nagatsu K, Fukada M, Hanyu M, Zhang MR. Development of a remote purification apparatus with disposable evaporator for the routine production of high-quality 64Cu for clinical use. Appl Radiat Isot 2019; 146:127-132. [DOI: 10.1016/j.apradiso.2019.01.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 01/25/2019] [Accepted: 01/26/2019] [Indexed: 10/27/2022]
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Schillaci O, Scimeca M, Trivigno D, Chiaravalloti A, Facchetti S, Anemona L, Bonfiglio R, Santeusanio G, Tancredi V, Bonanno E, Urbano N, Mauriello A. Prostate cancer and inflammation: A new molecular imaging challenge in the era of personalized medicine. Nucl Med Biol 2019; 68-69:66-79. [PMID: 30770226 DOI: 10.1016/j.nucmedbio.2019.01.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 12/23/2018] [Accepted: 01/14/2019] [Indexed: 12/21/2022]
Abstract
The relationship between cancer and inflammation is one of the most important fields for both clinical and translational research. Despite numerous studies reported interesting and solid data about the prognostic value of the presence of inflammatory infiltrate in cancers, the biological role of inflammation in prostate cancer development is not yet fully clarified. The characterization of molecular pathways that connect altered inflammatory response and prostate cancer progression can provide the scientific rationale for the identification of new prognostic and predictive biomarkers. Specifically, the detection of infiltrating immune cells or related-cytokines by histology and/or by molecular imaging techniques could profoundly change the management of prostate cancer patients. In this context, the anatomic pathology and imaging diagnostic teamwork can provide a valuable support for the validation of new targets for diagnosis and therapy of prostate cancer lesions associated to the inflammatory infiltrate. The aim of this review is to summarize the current literature about the role of molecular imaging technique and anatomic pathology in the study of the mutual interaction occurring between prostate cancer and inflammation. Specifically, we reported the more recent advances in molecular imaging and histological methods for the early detection of prostate lesions associated to the inflammatory infiltrate.
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Affiliation(s)
- Orazio Schillaci
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Via Montpellier 1, Rome 00133, Italy; IRCCS Neuromed, Pozzilli, Italy
| | - Manuel Scimeca
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Via Montpellier 1, Rome 00133, Italy; University of San Raffaele, Via di Val Cannuta 247, 00166 Rome, Italy.
| | - Donata Trivigno
- Department of Experimental Medicine and Surgery, University "Tor Vergata", Via Montpellier 1, Rome 00133, Italy
| | - Agostino Chiaravalloti
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Via Montpellier 1, Rome 00133, Italy; IRCCS Neuromed, Pozzilli, Italy
| | - Simone Facchetti
- Department of Experimental Medicine and Surgery, University "Tor Vergata", Via Montpellier 1, Rome 00133, Italy
| | - Lucia Anemona
- Department of Experimental Medicine and Surgery, University "Tor Vergata", Via Montpellier 1, Rome 00133, Italy
| | - Rita Bonfiglio
- Department of Experimental Medicine and Surgery, University "Tor Vergata", Via Montpellier 1, Rome 00133, Italy
| | - Giuseppe Santeusanio
- Department of Experimental Medicine and Surgery, University "Tor Vergata", Via Montpellier 1, Rome 00133, Italy
| | - Virginia Tancredi
- University of San Raffaele, Via di Val Cannuta 247, 00166 Rome, Italy; Department of Systems Medicine, School of Sport and Exercise Sciences, University of Rome "Tor Vergata", Rome, Italy
| | - Elena Bonanno
- Department of Experimental Medicine and Surgery, University "Tor Vergata", Via Montpellier 1, Rome 00133, Italy
| | - Nicoletta Urbano
- Nuclear Medicine, Policlinico "Tor Vergata", Viale Oxford 81, 00133 Rome, Italy
| | - Alessandro Mauriello
- Department of Experimental Medicine and Surgery, University "Tor Vergata", Via Montpellier 1, Rome 00133, Italy
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Shao S, Rajendiran V, Lovell JF. Metalloporphyrin Nanoparticles: Coordinating Diverse Theranostic Functions. Coord Chem Rev 2019; 379:99-120. [PMID: 30559508 PMCID: PMC6294123 DOI: 10.1016/j.ccr.2017.09.002] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Metalloporphyrins serve key roles in natural biological processes and also have demonstrated utility for biomedical applications. They can be encapsulated or grafted in conventional nanoparticles or can self-assemble themselves at the nanoscale. A wide range of metals can be stably chelated either before or after porphyrin nanoparticle formation, without the necessity of any additional chelator chemistry. The addition of metals can substantially alter a range of behaviors such as modulating phototherapeutic efficacy; conferring responsiveness to biological stimuli; or providing contrast for magnetic resonance, positron emission or surface enhanced Raman imaging. Chelated metals can also provide a convenient handle for bioconjugation with other molecules via axial coordination. This review provides an overview of some recent biomedical, nanoparticulate approaches involving gain-of-function metalloporphyrins and related molecules.
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Affiliation(s)
- Shuai Shao
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, USA
| | - Venugopal Rajendiran
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, USA
- Department of Chemistry, School of Basic and Applied Sciences, Central University of Tamil Nadu, Thiruvarur 610 005, India
| | - Jonathan F. Lovell
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, USA
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Abstract
Nuclear medicine is composed of two complementary areas, imaging and therapy. Positron emission tomography (PET) and single-photon imaging, including single-photon emission computed tomography (SPECT), comprise the imaging component of nuclear medicine. These areas are distinct in that they exploit different nuclear decay processes and also different imaging technologies. In PET, images are created from the 511 keV photons produced when the positron emitted by a radionuclide encounters an electron and is annihilated. In contrast, in single-photon imaging, images are created from the γ rays (and occasionally X-rays) directly emitted by the nucleus. Therapeutic nuclear medicine uses particulate radiation such as Auger or conversion electrons or β- or α particles. All three of these technologies are linked by the requirement that the radionuclide must be attached to a suitable vector that can deliver it to its target. It is imperative that the radionuclide remain attached to the vector before it is delivered to its target as well as after it reaches its target or else the resulting image (or therapeutic outcome) will not reflect the biological process of interest. Radiochemistry is at the core of this process, and radiometals offer radiopharmaceutical chemists a tremendous range of options with which to accomplish these goals. They also offer a wide range of options in terms of radionuclide half-lives and emission properties, providing the ability to carefully match the decay properties with the desired outcome. This Review provides an overview of some of the ways this can be accomplished as well as several historical examples of some of the limitations of earlier metalloradiopharmaceuticals and the ways that new technologies, primarily related to radionuclide production, have provided solutions to these problems.
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Affiliation(s)
- Eszter Boros
- Department of Chemistry , Stony Brook University , Stony Brook , New York 11794 , United States
| | - Alan B Packard
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology , Boston Children's Hospital , Boston , Massachusetts 02115 , United States.,Harvard Medical School , Boston , Massachusetts 02115 , United States
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