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1
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Maier A, Teunissen AJP, Nauta SA, Lutgens E, Fayad ZA, van Leent MMT. Uncovering atherosclerotic cardiovascular disease by PET imaging. Nat Rev Cardiol 2024; 21:632-651. [PMID: 38575752 PMCID: PMC11324396 DOI: 10.1038/s41569-024-01009-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/04/2024] [Indexed: 04/06/2024]
Abstract
Assessing atherosclerosis severity is essential for precise patient stratification. Specifically, there is a need to identify patients with residual inflammation because these patients remain at high risk of cardiovascular events despite optimal management of cardiovascular risk factors. Molecular imaging techniques, such as PET, can have an essential role in this context. PET imaging can indicate tissue-based disease status, detect early molecular changes and provide whole-body information. Advances in molecular biology and bioinformatics continue to help to decipher the complex pathogenesis of atherosclerosis and inform the development of imaging tracers. Concomitant advances in tracer synthesis methods and PET imaging technology provide future possibilities for atherosclerosis imaging. In this Review, we summarize the latest developments in PET imaging techniques and technologies for assessment of atherosclerotic cardiovascular disease and discuss the relationship between imaging readouts and transcriptomics-based plaque phenotyping.
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Affiliation(s)
- Alexander Maier
- Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Abraham J P Teunissen
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sheqouia A Nauta
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Esther Lutgens
- Cardiovascular Medicine and Immunology, Experimental Cardiovascular Immunology Laboratory, Mayo Clinic, Rochester, MN, USA
| | - Zahi A Fayad
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mandy M T van Leent
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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2
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Li Y, Chen L, Papadopoulos V. The mitochondrial translocator protein (TSPO, 18 kDa): A key multifunctional molecule in liver diseases. Biochimie 2024; 224:91-103. [PMID: 38065288 DOI: 10.1016/j.biochi.2023.11.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/23/2023] [Accepted: 11/29/2023] [Indexed: 08/23/2024]
Abstract
Translocator protein (TSPO, 18 kDa), previously known as peripheral-type benzodiazepine receptor, is an evolutionarily conserved and tryptophan-rich 169-amino-acid protein located on the outer mitochondrial membrane. TSPO plays a crucial role in various fundamental physiological functions and cellular processes. Its expression is altered in pathological conditions, thus rendering TSPO a potential tool for diagnostic imaging and an appealing therapeutic target. The investigation of synthetic TSPO ligands as both agonists and antagonists has provided valuable insights into the regulatory mechanisms and functional properties of TSPO. Recently, accumulating evidence has highlighted the significance of TSPO in liver diseases. However, a comprehensive summary of TSPO function in the normal liver and diverse liver diseases is lacking. This review aims to provide an overview of recent advances in understanding TSPO function in both normal liver cells and various liver diseases, with a particular emphasis on its involvement in liver fibrosis and inflammation and addresses the existing knowledge gaps in the field that require further investigation.
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Affiliation(s)
- Yuchang Li
- Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
| | - Liting Chen
- Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Vassilios Papadopoulos
- Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
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3
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Jiao J, Hu B, Mou T, Li Q, Tian Y, Zhang N, Zhang Y, Yun M, Nan N, Tian J, Yu W, Mi H, Dong W, Song X. Translocator Protein 18 kDa Tracer 18F-FDPA PET/CTA Imaging for the Evaluation of Inflammation in Vulnerable Plaques. Mol Pharm 2024; 21:3623-3633. [PMID: 38819959 DOI: 10.1021/acs.molpharmaceut.4c00344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2024]
Abstract
Inflammation induced by activated macrophages within vulnerable atherosclerotic plaques (VAPs) constitutes a significant risk factor for plaque rupture. Translocator protein (TSPO) is highly expressed in activated macrophages. This study investigated the effectiveness of TSPO radiotracers, 18F-FDPA, in detecting VAPs and quantifying plaque inflammation in rabbits. 18 New Zealand rabbits were divided into 3 groups: sham group A, VAP model group B, and evolocumab treatment group C. 18F-FDPA PET/CTA imaging was performed at 12, 16, and 24 weeks in all groups. Optical coherence tomography (OCT) was performed on the abdominal aorta at 24 weeks. The VAP was defined through OCT images, and ex vivo aorta PET imaging was also performed at 24 weeks. The SUVmax and SUVmean of 18F-FDPA were measured on the target organ, and the target-to-background ratio (TBRmax) was calculated as SUVmax/SUVblood pool. The arterial sections of the isolated abdominal aorta were analyzed by HE staining, CD68 and TSPO immunofluorescence staining, and TSPO Western blot. The results showed that at 24 weeks, the plaque TBRmax of 18F-FDPA in group B was significantly higher than in groups A and C. Immunofluorescence staining of CD68 and TSPO, as well as Western blot, confirmed the increased expression of macrophages and TSPO in the corresponding regions of group B. HE staining revealed an increased presence of the lipid core, multiple foam cells, and inflammatory cell infiltration in the area with high 18F-FDPA uptake. This indicates a correlation between 18F-FDPA uptake, inflammation severity, and VAPs. The TSPO-targeted tracer 18F-FDPA shows specific uptake in macrophage-rich regions of atherosclerotic plaques, making it a valuable tool for assessing inflammation in VAPs.
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Affiliation(s)
- Jian Jiao
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Biao Hu
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Tiantian Mou
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Quan Li
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Yi Tian
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Nan Zhang
- Department of Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Ying Zhang
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Mingkai Yun
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Nan Nan
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Jing Tian
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Wei Yu
- Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Hongzhi Mi
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Wei Dong
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Xiantao Song
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
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4
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Baglini E, Poggetti V, Cavallini C, Petroni D, Forini F, Nicolini G, Barresi E, Salerno S, Costa B, Iozzo P, Neglia D, Menichetti L, Taliani S, Da Settimo F. Targeting the Translocator Protein (18 kDa) in Cardiac Diseases: State of the Art and Future Opportunities. J Med Chem 2024; 67:17-37. [PMID: 38113353 PMCID: PMC10911791 DOI: 10.1021/acs.jmedchem.3c01716] [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: 09/15/2023] [Revised: 11/16/2023] [Accepted: 11/24/2023] [Indexed: 12/21/2023]
Abstract
Mitochondria dysfunctions are typical hallmarks of cardiac disorders (CDs). The multiple tasks of this energy-producing organelle are well documented, but its pathophysiologic involvement in several manifestations of heart diseases, such as altered electromechanical coupling, excitability, and arrhythmias, is still under investigation. The human 18 kDa translocator protein (TSPO) is a protein located on the outer mitochondrial membrane whose expression is altered in different pathological conditions, including CDs, making it an attractive therapeutic and diagnostic target. Currently, only a few TSPO ligands are employed in CDs and cardiac imaging. In this Perspective, we report an overview of the emerging role of TSPO at the heart level, focusing on the recent literature concerning the development of TSPO ligands used for fighting and imaging heart-related disease conditions. Accordingly, targeting TSPO might represent a successful strategy to achieve novel therapeutic and diagnostic strategies to unravel the fundamental mechanisms and to provide solutions to still unanswered questions in CDs.
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Affiliation(s)
- Emma Baglini
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Valeria Poggetti
- Department
of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy
| | - Chiara Cavallini
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Debora Petroni
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Francesca Forini
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Giuseppina Nicolini
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Elisabetta Barresi
- Department
of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy
| | - Silvia Salerno
- Department
of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy
| | - Barbara Costa
- Department
of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy
| | - Patricia Iozzo
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Danilo Neglia
- Fondazione
CNR/Regione Toscana Gabriele Monasterio, Cardiovascular and Imaging
Departments, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Luca Menichetti
- Institute
of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy
| | - Sabrina Taliani
- Department
of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy
| | - Federico Da Settimo
- Department
of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy
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5
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Xia W, Singh N, Goel S, Shi S. Molecular Imaging of Innate Immunity and Immunotherapy. Adv Drug Deliv Rev 2023; 198:114865. [PMID: 37182699 DOI: 10.1016/j.addr.2023.114865] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/17/2023] [Accepted: 05/03/2023] [Indexed: 05/16/2023]
Abstract
The innate immune system plays a key role as the first line of defense in various human diseases including cancer, cardiovascular and inflammatory diseases. In contrast to tissue biopsies and blood biopsies, in vivo imaging of the innate immune system can provide whole body measurements of immune cell location and function and changes in response to disease progression and therapy. Rationally developed molecular imaging strategies can be used in evaluating the status and spatio-temporal distributions of the innate immune cells in near real-time, mapping the biodistribution of novel innate immunotherapies, monitoring their efficacy and potential toxicities, and eventually for stratifying patients that are likely to benefit from these immunotherapies. In this review, we will highlight the current state-of-the-art in noninvasive imaging techniques for preclinical imaging of the innate immune system particularly focusing on cell trafficking, biodistribution, as well as pharmacokinetics and dynamics of promising immunotherapies in cancer and other diseases; discuss the unmet needs and current challenges in integrating imaging modalities and immunology and suggest potential solutions to overcome these barriers.
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Affiliation(s)
- Wenxi Xia
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, United States
| | - Neetu Singh
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, United States
| | - Shreya Goel
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, United States; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, United States; Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84112, United States
| | - Sixiang Shi
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, United States; Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84112, United States.
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6
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Tang JM, McClennan A, Liu L, Hadway J, Ronald JA, Hicks JW, Hoffman L, Anazodo UC. A Protocol for Simultaneous In Vivo Imaging of Cardiac and Neuroinflammation in Dystrophin-Deficient MDX Mice Using [ 18F]FEPPA PET. Int J Mol Sci 2023; 24:ijms24087522. [PMID: 37108685 PMCID: PMC10144317 DOI: 10.3390/ijms24087522] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 04/14/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by dystrophin loss-notably within muscles and the central neurons system. DMD presents as cognitive weakness, progressive skeletal and cardiac muscle degeneration until pre-mature death from cardiac or respiratory failure. Innovative therapies have improved life expectancy; however, this is accompanied by increased late-onset heart failure and emergent cognitive degeneration. Thus, better assessment of dystrophic heart and brain pathophysiology is needed. Chronic inflammation is strongly associated with skeletal and cardiac muscle degeneration; however, neuroinflammation's role is largely unknown in DMD despite being prevalent in other neurodegenerative diseases. Here, we present an inflammatory marker translocator protein (TSPO) positron emission tomography (PET) protocol for in vivo concomitant assessment of immune cell response in hearts and brains of a dystrophin-deficient mouse model [mdx:utrn(+/-)]. Preliminary analysis of whole-body PET imaging using the TSPO radiotracer, [18F]FEPPA in four mdx:utrn(+/-) and six wildtype mice are presented with ex vivo TSPO-immunofluorescence tissue staining. The mdx:utrn(+/-) mice showed significant elevations in heart and brain [18F]FEPPA activity, which correlated with increased ex vivo fluorescence intensity, highlighting the potential of TSPO-PET to simultaneously assess presence of cardiac and neuroinflammation in dystrophic heart and brain, as well as in several organs within a DMD model.
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Affiliation(s)
- Joanne M Tang
- Department of Medical Biophysics, Western University, London, ON N6A 3K7, Canada
- Lawson Health Research Institute, London, ON N6A 4V2, Canada
| | - Andrew McClennan
- Department of Medical Biophysics, Western University, London, ON N6A 3K7, Canada
- Lawson Health Research Institute, London, ON N6A 4V2, Canada
| | - Linshan Liu
- Lawson Health Research Institute, London, ON N6A 4V2, Canada
| | - Jennifer Hadway
- Lawson Health Research Institute, London, ON N6A 4V2, Canada
| | - John A Ronald
- Department of Medical Biophysics, Western University, London, ON N6A 3K7, Canada
- Robarts Research Institute, Western University, London, ON N6A 3K7, Canada
| | - Justin W Hicks
- Department of Medical Biophysics, Western University, London, ON N6A 3K7, Canada
- Lawson Health Research Institute, London, ON N6A 4V2, Canada
| | - Lisa Hoffman
- Department of Medical Biophysics, Western University, London, ON N6A 3K7, Canada
- Lawson Health Research Institute, London, ON N6A 4V2, Canada
- Department of Anatomy and Cell Biology, Western University, London, ON N6A 3K7, Canada
| | - Udunna C Anazodo
- Department of Medical Biophysics, Western University, London, ON N6A 3K7, Canada
- Lawson Health Research Institute, London, ON N6A 4V2, Canada
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 0G4, Canada
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7
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Nakahara T, Strauss HW, Narula J, Jinzaki M. Vulnerable Plaque Imaging. Semin Nucl Med 2023; 53:230-240. [PMID: 36333157 DOI: 10.1053/j.semnuclmed.2022.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/27/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022]
Abstract
Atherosclerotic plaques progress as a result of inflammation. Both invasive and noninvasive imaging techniques have been developed to identify and characterize plaque as vulnerable (more likely to rupture and cause a clinical event). Imaging techniques to identify vulnerable include identifying vessels with focal subendothelial collections of I) inflammatory cells; II) lipid/ fatty acid; III) local regions of hypoxia; IV) local expression of angiogenesis factors; V) local expression of protease; VI) intravascular foci of thrombus; hemorrhage (most often seen in the aftermath of a clinical event); VII) apoptosis and VIII) microcalcification. This review provides an overview of atherosclerotic plaque progression and tracers which can visualize specific molecules associated with vulnerability.
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Affiliation(s)
- Takehiro Nakahara
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan.
| | - H William Strauss
- Division of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jagat Narula
- Division of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Mahahiro Jinzaki
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan
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8
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Parry R, Majeed K, Pixley F, Hillis GS, Francis RJ, Schultz CJ. Unravelling the role of macrophages in cardiovascular inflammation through imaging: a state-of-the-art review. Eur Heart J Cardiovasc Imaging 2022; 23:e504-e525. [PMID: 35993316 PMCID: PMC9671294 DOI: 10.1093/ehjci/jeac167] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 07/31/2022] [Indexed: 11/13/2022] Open
Abstract
Cardiovascular disease remains the leading cause of death and disability for patients across the world. Our understanding of atherosclerosis as a primary cholesterol issue has diversified, with a significant dysregulated inflammatory component that largely remains untreated and continues to drive persistent cardiovascular risk. Macrophages are central to atherosclerotic inflammation, and they exist along a functional spectrum between pro-inflammatory and anti-inflammatory extremes. Recent clinical trials have demonstrated a reduction in major cardiovascular events with some, but not all, anti-inflammatory therapies. The recent addition of colchicine to societal guidelines for the prevention of recurrent cardiovascular events in high-risk patients with chronic coronary syndromes highlights the real-world utility of this class of therapies. A highly targeted approach to modification of interleukin-1-dependent pathways shows promise with several novel agents in development, although excessive immunosuppression and resulting serious infection have proven a barrier to implementation into clinical practice. Current risk stratification tools to identify high-risk patients for secondary prevention are either inadequately robust or prohibitively expensive and invasive. A non-invasive and relatively inexpensive method to identify patients who will benefit most from novel anti-inflammatory therapies is required, a role likely to be fulfilled by functional imaging methods. This review article outlines our current understanding of the inflammatory biology of atherosclerosis, upcoming therapies and recent landmark clinical trials, imaging modalities (both invasive and non-invasive) and the current landscape surrounding functional imaging including through targeted nuclear and nanobody tracer development and their application.
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Affiliation(s)
- Reece Parry
- School of Medicine, University of Western Australia, Perth 6009, Australia
- Department of Cardiology, Royal Perth Hospital, 197 Wellington Street, Perth, WA 6000, Australia
| | - Kamran Majeed
- School of Medicine, University of Western Australia, Perth 6009, Australia
- Department of Cardiology, Waikato District Health Board, Hamilton 3204, New Zealand
| | - Fiona Pixley
- School of Biomedical Sciences, Pharmacology and Toxicology, University of Western Australia, Perth 6009, Australia
| | - Graham Scott Hillis
- School of Medicine, University of Western Australia, Perth 6009, Australia
- Department of Cardiology, Royal Perth Hospital, 197 Wellington Street, Perth, WA 6000, Australia
| | - Roslyn Jane Francis
- School of Medicine, University of Western Australia, Perth 6009, Australia
- Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth 6009, Australia
| | - Carl Johann Schultz
- School of Medicine, University of Western Australia, Perth 6009, Australia
- Department of Cardiology, Royal Perth Hospital, 197 Wellington Street, Perth, WA 6000, Australia
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9
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van der Geest KSM, Sandovici M, Nienhuis PH, Slart RHJA, Heeringa P, Brouwer E, Jiemy WF. Novel PET Imaging of Inflammatory Targets and Cells for the Diagnosis and Monitoring of Giant Cell Arteritis and Polymyalgia Rheumatica. Front Med (Lausanne) 2022; 9:902155. [PMID: 35733858 PMCID: PMC9207253 DOI: 10.3389/fmed.2022.902155] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/13/2022] [Indexed: 12/26/2022] Open
Abstract
Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are two interrelated inflammatory diseases affecting patients above 50 years of age. Patients with GCA suffer from granulomatous inflammation of medium- to large-sized arteries. This inflammation can lead to severe ischemic complications (e.g., irreversible vision loss and stroke) and aneurysm-related complications (such as aortic dissection). On the other hand, patients suffering from PMR present with proximal stiffness and pain due to inflammation of the shoulder and pelvic girdles. PMR is observed in 40-60% of patients with GCA, while up to 21% of patients suffering from PMR are also affected by GCA. Due to the risk of ischemic complications, GCA has to be promptly treated upon clinical suspicion. The treatment of both GCA and PMR still heavily relies on glucocorticoids (GCs), although novel targeted therapies are emerging. Imaging has a central position in the diagnosis of GCA and PMR. While [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) has proven to be a valuable tool for diagnosis of GCA and PMR, it possesses major drawbacks such as unspecific uptake in cells with high glucose metabolism, high background activity in several non-target organs and a decrease of diagnostic accuracy already after a short course of GC treatment. In recent years, our understanding of the immunopathogenesis of GCA and, to some extent, PMR has advanced. In this review, we summarize the current knowledge on the cellular heterogeneity in the immunopathology of GCA/PMR and discuss how recent advances in specific tissue infiltrating leukocyte and stromal cell profiles may be exploited as a source of novel targets for imaging. Finally, we discuss prospective novel PET radiotracers that may be useful for the diagnosis and treatment monitoring in GCA and PMR.
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Affiliation(s)
- Kornelis S. M. van der Geest
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Maria Sandovici
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Pieter H. Nienhuis
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Riemer H. J. A. Slart
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- Department of Biomedical Photonic Imaging Group, University of Twente, Enschede, Netherlands
| | - Peter Heeringa
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Elisabeth Brouwer
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - William F. Jiemy
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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10
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Crișan G, Moldovean-Cioroianu NS, Timaru DG, Andrieș G, Căinap C, Chiș V. Radiopharmaceuticals for PET and SPECT Imaging: A Literature Review over the Last Decade. Int J Mol Sci 2022; 23:5023. [PMID: 35563414 PMCID: PMC9103893 DOI: 10.3390/ijms23095023] [Citation(s) in RCA: 110] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 04/23/2022] [Accepted: 04/28/2022] [Indexed: 02/04/2023] Open
Abstract
Positron emission tomography (PET) uses radioactive tracers and enables the functional imaging of several metabolic processes, blood flow measurements, regional chemical composition, and/or chemical absorption. Depending on the targeted processes within the living organism, different tracers are used for various medical conditions, such as cancer, particular brain pathologies, cardiac events, and bone lesions, where the most commonly used tracers are radiolabeled with 18F (e.g., [18F]-FDG and NA [18F]). Oxygen-15 isotope is mostly involved in blood flow measurements, whereas a wide array of 11C-based compounds have also been developed for neuronal disorders according to the affected neuroreceptors, prostate cancer, and lung carcinomas. In contrast, the single-photon emission computed tomography (SPECT) technique uses gamma-emitting radioisotopes and can be used to diagnose strokes, seizures, bone illnesses, and infections by gauging the blood flow and radio distribution within tissues and organs. The radioisotopes typically used in SPECT imaging are iodine-123, technetium-99m, xenon-133, thallium-201, and indium-111. This systematic review article aims to clarify and disseminate the available scientific literature focused on PET/SPECT radiotracers and to provide an overview of the conducted research within the past decade, with an additional focus on the novel radiopharmaceuticals developed for medical imaging.
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Affiliation(s)
- George Crișan
- Faculty of Physics, Babeş-Bolyai University, Str. M. Kogălniceanu 1, 400084 Cluj-Napoca, Romania; (G.C.); (N.S.M.-C.); (D.-G.T.)
- Department of Nuclear Medicine, County Clinical Hospital, Clinicilor 3-5, 400006 Cluj-Napoca, Romania;
| | | | - Diana-Gabriela Timaru
- Faculty of Physics, Babeş-Bolyai University, Str. M. Kogălniceanu 1, 400084 Cluj-Napoca, Romania; (G.C.); (N.S.M.-C.); (D.-G.T.)
| | - Gabriel Andrieș
- Department of Nuclear Medicine, County Clinical Hospital, Clinicilor 3-5, 400006 Cluj-Napoca, Romania;
| | - Călin Căinap
- The Oncology Institute “Prof. Dr. Ion Chiricuţă”, Republicii 34-36, 400015 Cluj-Napoca, Romania;
| | - Vasile Chiș
- Faculty of Physics, Babeş-Bolyai University, Str. M. Kogălniceanu 1, 400084 Cluj-Napoca, Romania; (G.C.); (N.S.M.-C.); (D.-G.T.)
- Institute for Research, Development and Innovation in Applied Natural Sciences, Babeș-Bolyai University, Str. Fântânele 30, 400327 Cluj-Napoca, Romania
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11
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Molecular Imaging of Vulnerable Coronary Plaque with Radiolabeled Somatostatin Receptors (SSTR). J Clin Med 2021; 10:jcm10235515. [PMID: 34884218 PMCID: PMC8658082 DOI: 10.3390/jcm10235515] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/21/2021] [Accepted: 11/23/2021] [Indexed: 12/25/2022] Open
Abstract
Atherosclerosis is responsible for the majority of heart attacks and is characterized by several modifications of the arterial wall including an inflammatory reaction. The silent course of atherosclerosis has made it necessary to develop predictors of disease complications before symptomatic lesions occur. Vulnerable to rupture atherosclerotic plaques are the target for molecular imaging. To this aim, different radiopharmaceuticals for PET/CT have emerged for the identification of high-risk plaques, with high specificity for the identification of the cellular components and pathophysiological status of plaques. By targeting specific receptors on activated macrophages in high-risk plaques, radiolabelled somatostatin analogues such as 68Ga-DOTA-TOC, TATE,0 or NOC have shown high relevance to detect vulnerable, atherosclerotic plaques. This PET radiopharmaceutical has been tested in several pre-clinical and clinical studies, as reviewed here, showing an important correlation with other risk factors.
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12
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Maekawa K, Tsuji AB, Yamashita A, Sugyo A, Katoh C, Tang M, Nishihira K, Shibata Y, Koshimoto C, Zhang MR, Nishii R, Yoshinaga K, Asada Y. Translocator protein imaging with 18F-FEDAC-positron emission tomography in rabbit atherosclerosis and its presence in human coronary vulnerable plaques. Atherosclerosis 2021; 337:7-17. [PMID: 34662838 DOI: 10.1016/j.atherosclerosis.2021.10.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 08/20/2021] [Accepted: 10/08/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND AIMS This study aimed to investigate whether N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[18F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide (18F-FEDAC), a probe for translocator protein (TSPO), can visualize atherosclerotic lesions in rabbits and whether TSPO is localized in human coronary plaques. METHODS 18F-FEDAC-PET of a rabbit model of atherosclerosis induced by a 0.5% cholesterol diet and balloon injury of the left carotid artery (n = 7) was performed eight weeks after the injury. The autoradiography intensity of 18F-FEDAC in carotid artery tissue sections was measured, and TSPO expression was evaluated immunohistochemically. TSPO expression was examined in human coronary arteries obtained from autopsy cases (n = 16), and in human coronary plaques (n = 12) aspirated from patients with acute myocardial infarction (AMI). RESULTS 18F-FEDAC-PET visualized the atherosclerotic lesions in rabbits as high-uptake areas, and the standard uptake value was higher in injured arteries (0.574 ± 0.24) than in uninjured arteries (0.277 ± 0.13, p < 0.05) or myocardium (0.189 ± 0.07, p < 0.05). Immunostaining showed more macrophages and more TSPO expression in atherosclerotic lesions than in uninjured arteries. TSPO was localized in macrophages, and arterial autoradiography intensity was positively correlated with macrophage concentration (r = 0.64) and TSPO (r = 0.67). TSPO expression in human coronary arteries was higher in AMI cases than in non-cardiac death, or in the vulnerable plaques than in early or stable lesions, respectively. TSPO was localized in macrophages in all aspirated coronary plaques with thrombi. CONCLUSIONS 18F-FEDAC-PET can visualize atherosclerotic lesions, and TSPO-expression may be a marker of high-risk coronary plaques.
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Affiliation(s)
- Kazunari Maekawa
- Department of Pathology, Faculty of Medicine, University of Miyazaki, 889-1692, 5200, Kihara, Kiyotake, Miyazaki City, Miyazaki, Japan
| | - Atsushi B Tsuji
- Diagnostic and Therapeutic Nuclear Medicine, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 263-8555, 4-9, Anagawa, Inage, Chiba City, Chiba, Japan
| | - Atsushi Yamashita
- Department of Pathology, Faculty of Medicine, University of Miyazaki, 889-1692, 5200, Kihara, Kiyotake, Miyazaki City, Miyazaki, Japan.
| | - Aya Sugyo
- Diagnostic and Therapeutic Nuclear Medicine, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 263-8555, 4-9, Anagawa, Inage, Chiba City, Chiba, Japan
| | - Chietsugu Katoh
- Department of Biomedical Science and Engineering, Faculty of Health Sciences, Hokkaido University, 060-0812, 5, 12Jo-Nishi, Kita, Kita-Ku, Sapporo City, Hokkaido, Japan
| | - Minghui Tang
- Department of Biomedical Science and Engineering, Faculty of Health Sciences, Hokkaido University, 060-0812, 5, 12Jo-Nishi, Kita, Kita-Ku, Sapporo City, Hokkaido, Japan
| | - Kensaku Nishihira
- Department of Cardiology, Miyazaki Medical Association Hospital, 880-2102, 1173, Arita, Miyazaki City, Miyazaki, Japan
| | - Yoshisato Shibata
- Department of Cardiology, Miyazaki Medical Association Hospital, 880-2102, 1173, Arita, Miyazaki City, Miyazaki, Japan
| | - Chihiro Koshimoto
- Frontier Science Research Center, University of Miyazaki, 889-1692, 5200, Kihara, Kiyotake, Miyazaki City, Miyazaki, Japan
| | - Ming-Rong Zhang
- Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 263-8555, 4-9, Anagawa, Inage, Chiba City, Chiba, Japan
| | - Ryuichi Nishii
- Diagnostic and Therapeutic Nuclear Medicine, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 263-8555, 4-9, Anagawa, Inage, Chiba City, Chiba, Japan
| | - Keiichiro Yoshinaga
- Diagnostic and Therapeutic Nuclear Medicine, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 263-8555, 4-9, Anagawa, Inage, Chiba City, Chiba, Japan
| | - Yujiro Asada
- Department of Pathology, Faculty of Medicine, University of Miyazaki, 889-1692, 5200, Kihara, Kiyotake, Miyazaki City, Miyazaki, Japan
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13
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Schollhammer R, Lepreux S, Barthe N, Vimont D, Rullier A, Sibon I, Berard X, Zhang A, Kimura Y, Fujita M, Innis RB, Zanotti-Fregonara P, Morgat C. In vitro and pilot in vivo imaging of 18 kDa translocator protein (TSPO) in inflammatory vascular disease. EJNMMI Res 2021; 11:45. [PMID: 33950298 PMCID: PMC8099943 DOI: 10.1186/s13550-021-00786-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/27/2021] [Indexed: 11/25/2022] Open
Abstract
Background Inflammatory vascular disease of the arteries, such as inflamed atheromatous plaques or arteritis, may cause aneurysms or ischemic strokes. In this context, using positron emission tomography (PET) to image inflammation may help select patients who would benefit from appropriate therapeutic interventions. This study sought to assess the usefulness of the 18 kDa translocator protein (TSPO) tracers [11C]-PBR28 and [18F]-PBR06 for imaging inflammatory vascular disease in vitro and in vivo. Immunohistochemistry for macrophage infiltration as well as autoradiography with [18F]-PBR06 were performed on eight paraffin-embedded, formalin-fixed atherosclerosis plaques prospectively collected after carotid endarterectomy of eight patients affected by ischemic stroke. Six different patients, one of whom was also included in the in vitro study, underwent PET imaging. Two patients with carotid stenosis associated with ischemic stroke were imaged with [18F]-PBR06 PET/CT, and four other patients (three with large vessel vasculitis and one with bilateral carotid stenosis but without stroke) were imaged with [11C]-PBR28. Results All in vitro sections showed specific binding of [18F]-PBR06, which co-localized with immunohistochemistry markers for inflammation. However, in vivo TSPO imaging with either [11C]-PBR28 or [18F]-PBR06 was negative in all participants. Conclusion Despite good uptake on surgical samples in vitro, [11C]-PBR28 and [18F]-PBR06 are not viable clinical tools for imaging inflammatory vascular disease. Trial registration: NCT02513589, registered 31 July 2015 and NCT00547976, registered 23 October 2007. https://clinicaltrials.gov.
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Affiliation(s)
- Romain Schollhammer
- Nuclear Medicine Department, University Hospital of Bordeaux, 33076, Bordeaux, France. .,University of Bordeaux, INCIA, UMR5287, 33400, Talence, France. .,CNRS, INCIA, UMR5287, 33400, Talence, France. .,Nuclear Medicine Department, University Hospital of Bordeaux, Place Amélie Raba Léon, 33000, Bordeaux, France.
| | | | | | - Delphine Vimont
- University of Bordeaux, INCIA, UMR5287, 33400, Talence, France.,CNRS, INCIA, UMR5287, 33400, Talence, France
| | - Anne Rullier
- Histologic Department, University Hospital of Bordeaux, 33076, Bordeaux, France
| | - Igor Sibon
- Neurology Department, University Hospital of Bordeaux, 33076, Bordeaux, France
| | - Xavier Berard
- Vascular Surgery Department, University Hospital of Bordeaux, 33076, Bordeaux, France
| | - Andrea Zhang
- Molecular Imaging Branch, NIMH, Bethesda, MD, USA
| | | | | | | | | | - Clément Morgat
- Nuclear Medicine Department, University Hospital of Bordeaux, 33076, Bordeaux, France.,University of Bordeaux, INCIA, UMR5287, 33400, Talence, France.,CNRS, INCIA, UMR5287, 33400, Talence, France
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14
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Adhikari A, Singh P, Mahar KS, Adhikari M, Adhikari B, Zhang MR, Tiwari AK. Mapping of Translocator Protein (18 kDa) in Peripheral Sterile Inflammatory Disease and Cancer through PET Imaging. Mol Pharm 2021; 18:1507-1529. [PMID: 33645995 DOI: 10.1021/acs.molpharmaceut.1c00002] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Positron emission tomography (PET) imaging of the translocator 18 kDa protein (TSPO) with radioligands has become an effective means of research in peripheral inflammatory conditions that occur in many diseases and cancers. The peripheral sterile inflammatory diseases (PSIDs) are associated with a diverse group of disorders that comprises numerous enduring insults including the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system. TSPO has recently been introduced as a potential biomarker for peripheral sterile inflammatory diseases (PSIDs). The major critical issue related to PSIDs is its timely characterization and localization of inflammatory foci for proper therapy of patients. As an alternative to metabolic imaging, protein imaging expressed on immune cells after activation is of great importance. The five transmembrane domain translocator protein-18 kDa (TSPO) is upregulated on the mitochondrial cell surface of macrophages during inflammation, serving as a potential ligand for PET tracers. Additionally, the overexpressed TSPO protein has been positively correlated with various tumor malignancies. In view of the association of escalated TSPO expression in both disease conditions, it is an immensely important biomarker for PET imaging in oncology and PSIDs. In this review, we summarize the most outstanding advances on TSPO-targeted PSIDs and cancer in the development of TSPO ligands as a potential diagnostic tool, specifically discussing the last five years.
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Affiliation(s)
- Anupriya Adhikari
- Department of Chemistry, Babasaheb Bhimrao Ambedkar University, (A Central University), Lucknow, Uttar Pradesh 226025, India
| | - Priya Singh
- Department of Chemistry, Babasaheb Bhimrao Ambedkar University, A Central University, Lucknow, Uttar Pradesh 226025, India
| | - Kamalesh S Mahar
- Birbal Sahni Institute of Palaeosciences, Lucknow, Uttar Pradesh 226007, India
| | - Manish Adhikari
- The George Washington University, Washington, D.C. 20052, United States
| | - Bhawana Adhikari
- Plasma Bio-science Research Center, Kwangwoon University, Seoul 01897, South Korea
| | - Ming-Rong Zhang
- Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Anjani Kumar Tiwari
- Department of Chemistry, Babasaheb Bhimrao Ambedkar University, (A Central University), Lucknow, Uttar Pradesh 226025, India
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15
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Ćorović A, Wall C, Mason JC, Rudd JHF, Tarkin JM. Novel Positron Emission Tomography Tracers for Imaging Vascular Inflammation. Curr Cardiol Rep 2020; 22:119. [PMID: 32772188 PMCID: PMC7415747 DOI: 10.1007/s11886-020-01372-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Purpose of Review To provide a focused update on recent advances in positron emission tomography (PET) imaging in vascular inflammatory diseases and consider future directions in the field. Recent Findings While PET imaging with 18F-fluorodeoxyglucose (FDG) can provide a useful marker of disease activity in several vascular inflammatory diseases, including atherosclerosis and large-vessel vasculitis, this tracer lacks inflammatory cell specificity and is not a practical solution for imaging the coronary vasculature because of avid background myocardial signal. To overcome these limitations, research is ongoing to identify novel PET tracers that can more accurately track individual components of vascular immune responses. Use of these novel PET tracers could lead to a better understanding of underlying disease mechanisms and help inform the identification and stratification of patients for newly emerging immune-modulatory therapies. Summary Future research is needed to realise the true clinical translational value of PET imaging in vascular inflammatory diseases.
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Affiliation(s)
- Andrej Ćorović
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
| | - Christopher Wall
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
| | - Justin C Mason
- Cardiovascular Division, National Heart & Lung Institute, Imperial College London, London, UK
| | - James H F Rudd
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
| | - Jason M Tarkin
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK. .,Cardiovascular Division, National Heart & Lung Institute, Imperial College London, London, UK.
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16
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17
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Heo GS, Sultan D, Liu Y. Current and novel radiopharmaceuticals for imaging cardiovascular inflammation. 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 RADIOPHARMACEUTICAL CHEMISTRY AND BIOLOGY 2020; 64:4-20. [PMID: 32077667 DOI: 10.23736/s1824-4785.20.03230-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Cardiovascular disease (CVD) remains the leading cause of death worldwide despite advances in diagnostic technologies and treatment strategies. The underlying cause of most CVD is atherosclerosis, a chronic disease driven by inflammatory reactions. Atherosclerotic plaque rupture could cause arterial occlusion leading to ischemic tissue injuries such as myocardial infarction (MI) and stroke. Clinically, most imaging modalities are based on anatomy and provide limited information about the on-going molecular activities affecting the vulnerability of atherosclerotic lesion for risk stratification of patients. Thus, the ability to differentiate stable plaques from those that are vulnerable is an unmet clinical need. Of various imaging techniques, the radionuclide-based molecular imaging modalities including positron emission tomography and single-photon emission computerized tomography provide superior ability to noninvasively visualize molecular activities in vivo and may serve as a useful tool in tackling this challenge. Moreover, the well-established translational pathway of radiopharmaceuticals may also facilitate the translation of discoveries from benchtop to clinical investigation in contrast to other imaging modalities to fulfill the goal of precision medicine. The relationship between inflammation occurring within the plaque and its proneness to rupture has been well documented. Therefore, an active effort has been significantly devoted to develop radiopharmaceuticals specifically to measure CVD inflammatory status, and potentially elucidate those plaques which are prone to rupture. In the following review, molecular imaging of inflammatory biomarkers will be briefly discussed.
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Affiliation(s)
- Gyu S Heo
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, USA
| | - Deborah Sultan
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, USA
| | - Yongjian Liu
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, USA -
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18
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MacAskill MG, Newby DE, Tavares AAS. Frontiers in positron emission tomography imaging of the vulnerable atherosclerotic plaque. Cardiovasc Res 2019; 115:1952-1962. [PMID: 31233100 PMCID: PMC6872971 DOI: 10.1093/cvr/cvz162] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 04/16/2019] [Accepted: 06/19/2019] [Indexed: 02/07/2023] Open
Abstract
Rupture of vulnerable atherosclerotic plaques leading to an atherothrombotic event is the primary driver of myocardial infarction and stroke. The ability to detect non-invasively the presence and evolution of vulnerable plaques could have a huge impact on the future identification and management of atherosclerotic cardiovascular disease. Positron emission tomography (PET) imaging with an appropriate radiotracer has the potential to achieve this goal. This review will discuss the biological hallmarks of plaque vulnerability before going on to evaluate and to present PET imaging approaches which target these processes. The focus of this review will be on techniques beyond [18F]FDG imaging, some of which are clinically advanced, and others which are on the horizon. As inflammation is the primary driving force behind atherosclerotic plaque development, we will predominantly focus on approaches which either directly, or indirectly, target this process.
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Affiliation(s)
- Mark G MacAskill
- University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
- Edinburgh Imaging, University of Edinburgh, Edinburgh, UK
| | - David E Newby
- University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Adriana A S Tavares
- University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
- Edinburgh Imaging, University of Edinburgh, Edinburgh, UK
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19
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Gui Y, Marks JD, Das S, Hyman BT, Serrano-Pozo A. Characterization of the 18 kDa translocator protein (TSPO) expression in post-mortem normal and Alzheimer's disease brains. Brain Pathol 2019; 30:151-164. [PMID: 31276244 PMCID: PMC6904423 DOI: 10.1111/bpa.12763] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 06/26/2019] [Indexed: 02/06/2023] Open
Abstract
The 18 kDa translocator protein (TSPO) is a widely used target for microglial PET imaging radioligands, but its expression in post-mortem normal and diseased human brain is not well described. We aimed at characterizing the TSPO expression in human control (CTRL) and Alzheimer's disease (AD) brains. Specifically, we sought to: (1) define the cell type(s) expressing TSPO; (2) compare tspo mRNA and TSPO levels between AD and CTRL brains; (3) correlate TSPO levels with quantitative neuropathological measures of reactive glia and AD neuropathological changes; and (4) investigate the effects of the TSPO rs6971 SNP on tspo mRNA and TSPO levels, glial responses and AD neuropathological changes. We performed quantitative immunohistochemistry and Western blot in post-mortem brain samples from CTRL and AD subjects, as well as analysis of publicly available mouse and human brain RNA-Seq datasets. We found that: (1) TSPO is expressed not just in microglia, but also in astrocytes, endothelial cells and vascular smooth muscle cells; (2) there is substantial overlap of tspo mRNA and TSPO levels between AD and CTRL subjects and in TSPO levels between temporal neocortex and white matter in both groups; (3) TSPO cortical burden does not correlate with the burden of activated microglia or reactive astrocytes, Aβ plaques or neurofibrillary tangles, or the cortical thickness; (4) the TSPO rs6971 SNP does not significantly impact tspo mRNA or TSPO levels, the magnitude of glial responses, the cortical thickness, or the burden of AD neuropathological changes. These results could inform ongoing efforts toward the development of reactive glia-specific PET radioligands.
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Affiliation(s)
- Yaxing Gui
- Department of Neurology, Massachusetts General Hospital, Boston, MA.,Department of Neurology, Sir Run Run Shaw Hospital of Zhejiang University, Zhejiang, China
| | - Jordan D Marks
- Department of Neurology, Massachusetts General Hospital, Boston, MA
| | - Sudeshna Das
- Department of Neurology, Massachusetts General Hospital, Boston, MA.,Harvard Medical School, Boston, MA
| | - Bradley T Hyman
- Department of Neurology, Massachusetts General Hospital, Boston, MA.,Harvard Medical School, Boston, MA
| | - Alberto Serrano-Pozo
- Department of Neurology, Massachusetts General Hospital, Boston, MA.,Harvard Medical School, Boston, MA
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20
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Jiemy WF, Heeringa P, Kamps JA, van der Laken CJ, Slart RH, Brouwer E. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of macrophages in large vessel vasculitis: Current status and future prospects. Autoimmun Rev 2018; 17:715-726. [PMID: 29729443 DOI: 10.1016/j.autrev.2018.02.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 02/07/2018] [Indexed: 12/21/2022]
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21
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Positron Emission Tomography Imaging of Macrophages in Atherosclerosis with 18F-GE-180, a Radiotracer for Translocator Protein (TSPO). CONTRAST MEDIA & MOLECULAR IMAGING 2018; 2018:9186902. [PMID: 29950954 PMCID: PMC5987326 DOI: 10.1155/2018/9186902] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 03/26/2018] [Accepted: 04/08/2018] [Indexed: 01/31/2023]
Abstract
Intraplaque inflammation plays an important role in the progression of atherosclerosis. The 18 kDa translocator protein (TSPO) expression is upregulated in activated macrophages, representing a potential target to identify inflamed atherosclerotic plaques. We preclinically evaluated 18F-GE-180, a novel third-generation TSPO radioligand, in a mouse model of atherosclerosis. Methods. Nine hypercholesterolemic mice deficient in low density lipoprotein receptor and apolipoprotein B48 (LDLR−/−ApoB100/100) and six healthy C57BL/6N mice were injected with 10 MBq of 18F-GE-180. Specificity of binding was demonstrated in three LDLR−/−ApoB100/100 mice by injection of nonradioactive reference compound of 18F-GE-180 before 18F-GE-180. Dynamic 30-minute PET was performed followed by contrast-enhanced CT, and the mice were sacrificed at 60 minutes after injection. Tissue samples were obtained for ex vivo biodistribution measurements, and aortas were cut into serial cryosections for digital autoradiography. The presence of macrophages and TSPO was studied by immunohistochemistry. The 18F-GE-180 retention in plaque areas with different macrophage densities and lesion-free vessel wall were compared. Results. The LDLR−/−ApoB100/100 mice showed large, inflamed plaques in the aorta. Autoradiography revealed significantly higher 18F-GE-180 retention in macrophage-rich plaque areas than in noninflamed areas (count densities 150 ± 45 PSL/mm2 versus 51 ± 12 PSL/mm2, p < 0.001). Prominent retention in the vessel wall without plaque was also observed (220 ± 41 PSL/mm2). Blocking with nonradioactive GE-180 diminished the difference in count densities between macrophage-rich and noninflamed areas in atherosclerotic plaques and lowered the count density in vessel wall without plaque. Conclusion. 18F-GE-180 shows specific uptake in macrophage-rich areas of atherosclerotic plaques in mice. However, retention in atherosclerotic lesions does not exceed that in lesion-free vessel wall. The third-generation TSPO radioligand 18F-GE-180 did not show improved characteristics for imaging atherosclerotic plaque inflammation compared to previously studied TSPO-targeting tracers.
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22
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Kupa LDVK, Drewes CC, Barioni ED, Neves CL, Sampaio SC, Farsky SHP. Role of Translocator 18 KDa Ligands in the Activation of Leukotriene B4 Activated G-Protein Coupled Receptor and Toll Like Receptor-4 Pathways in Neutrophils. Front Pharmacol 2017; 8:766. [PMID: 29163156 PMCID: PMC5664262 DOI: 10.3389/fphar.2017.00766] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 10/11/2017] [Indexed: 12/13/2022] Open
Abstract
TSPO (Translocator 18 KDa; tryptophan-rich sensory protein oxygen sensor) is a constitutive outer mitochondrial membrane protein overexpressed in inflammatory cells during local or systemic processes. Despite its expression is characterized, role of TSPO in inflammation remains elusive. For this study, we investigated the role of TSPO ligands on neutrophil functions elicited by two different inflammatory pathways. Peritoneal neutrophils were isolated from male Balb-C mice, treated with TSPO ligand diazepam, Ro5-4864 or PK11195 (1,100 or 1000 nM; 2 h) and further stimulated with lipopolysaccharide from Escherichia coli (LPS), a binding for Toll-Like Receptor-4 (TLR4), or leukotriene B4 (LTB4), a G-protein coupled receptor (GPCR) ligand. LPS treatment did not lead to overexpression of TSPO on neutrophils, and pre-treatment with any TSPO ligand did not alter cytokine expression, adhesion molecule expression, or the production of reactive oxygen and nitrogen species caused by LPS stimulation. Conversely, all TSPO ligands impaired LTB4’s actions, as visualized by reductions in L-selectin shedding, β2 integrin overexpression, neutrophil chemotaxis, and actin filament assembly. TSPO ligands showed distinct intracellular effects on LTB4-induced neutrophil locomotion, with diazepam enhancing cofilin but not modifying Arp2/3 expression, and Ro5-4864 and PK11195 reducing both cofilin and Arp2/3 expression. Taken together, our data exclude a direct role of TSPO ligands in TLR4-elicited pathways, and indicate that TSPO activation inhibits GPCR inflammatory pathways in neutrophils, with a relevant role in neutrophil influx into inflammatory sites.
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Affiliation(s)
- Léonard de Vinci Kanda Kupa
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Carine C Drewes
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Eric D Barioni
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Camila L Neves
- Laboratory of Pathophysiology, Institute Butantan, São Paulo, Brazil
| | | | - Sandra H P Farsky
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
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23
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TSPO PET Imaging: From Microglial Activation to Peripheral Sterile Inflammatory Diseases? CONTRAST MEDIA & MOLECULAR IMAGING 2017; 2017:6592139. [PMID: 29114179 PMCID: PMC5632884 DOI: 10.1155/2017/6592139] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 08/01/2017] [Accepted: 08/07/2017] [Indexed: 02/07/2023]
Abstract
Peripheral sterile inflammatory diseases (PSIDs) are a heterogeneous group of disorders that gathers several chronic insults involving the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system and wherein inflammation is the cornerstone of the pathophysiology. In PSID, timely characterization and localization of inflammatory foci are crucial for an adequate care for patients. In brain diseases, in vivo positron emission tomography (PET) exploration of inflammation has matured over the last 20 years, through the development of radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO) as molecular biomarkers of activated microglia. Recently, TSPO has been introduced as a possible molecular target for PSIDs PET imaging, making this protein a potential biomarker to address disease heterogeneity, to assist in patient stratification, and to contribute to predicting treatment response. In this review, we summarized the major research advances recently made in the field of TSPO PET imaging in PSIDs. Promising preliminary results have been reported in bowel, cardiovascular, and rheumatic inflammatory diseases, consolidated by preclinical studies. Limitations of TSPO PET imaging in PSIDs, regarding both its large expression in healthy peripheral tissues, unlike in central nervous system, and the production of peripheral radiolabeled metabolites, are also discussed, regarding their possible consequences on TSPO PET signal's quantification.
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Tsigkas N, Kidambi S, Tawakol A, Chatzizisis YS. Drug-loaded particles: “Trojan horses” in the therapy of atherosclerosis. Atherosclerosis 2016; 251:528-530. [DOI: 10.1016/j.atherosclerosis.2016.06.050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 06/29/2016] [Indexed: 02/07/2023]
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TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria. Biochem J 2016; 473:107-21. [PMID: 26733718 DOI: 10.1042/bj20150899] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.
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Graham A. Mitochondrial regulation of macrophage cholesterol homeostasis. Free Radic Biol Med 2015; 89:982-92. [PMID: 26416507 DOI: 10.1016/j.freeradbiomed.2015.08.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 07/28/2015] [Accepted: 08/11/2015] [Indexed: 12/19/2022]
Abstract
This review explores the relationship between mitochondrial structure and function in the regulation of macrophage cholesterol metabolism and proposes that mitochondrial dysfunction contributes to loss of the elegant homeostatic mechanisms which normally maintain cellular sterol levels within defined limits. Mitochondrial sterol 27-hydroxylase (CYP27A1) can generate oxysterol activators of liver X receptors which heterodimerise with retinoid X receptors, enhancing the transcription of ATP binding cassette transporters (ABCA1, ABCG1, and ABCG4), that can remove excess cholesterol via efflux to apolipoproteins A-1, E, and high density lipoprotein, and inhibit inflammation. The activity of CYP27A1 is regulated by the rate of supply of cholesterol substrate to the inner mitochondrial membrane, mediated by a complex of proteins. The precise identity of this dynamic complex remains controversial, even in steroidogenic tissues, but may include steroidogenic acute regulatory protein and the 18 kDa translocator protein, together with voltage-dependent anion channels, ATPase AAA domain containing protein 3A, and optic atrophy type 1 proteins. Certainly, overexpression of StAR and TSPO proteins can enhance macrophage cholesterol efflux to apoA-I and/or HDL, while perturbations in mitochondrial function, or changes in the expression of mitochondrial fusion proteins, alter the efficiency of cholesterol efflux. Molecules which can sustain or improve mitochondrial function or increase the activity of the protein complex involved in cholesterol transfer may have utility in resolving the problem of dysregulated macrophage cholesterol homeostasis, a condition which may contribute to inflammation, atherosclerosis, nonalcoholic steatohepatitis, osteoblastic bone resorption, and some disorders of the central nervous system.
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Affiliation(s)
- Annette Graham
- Department of Life Sciences, School of Health and Life Sciences, and Institute for Applied Health Research, Glasgow Caledonian University, 70 Cowcaddens Road, Glasgow G4 0BA, United Kingdom.
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Abstract
The mitochondrial 18-kDa translocator protein (TSPO) was originally discovered as a peripheral binding site of benzodiazepines to be later described as a core element of cholesterol trafficking between cytosol and mitochondria from which the current nomenclature originated. The high affinity it exhibits with chemicals (i.e. PK11195) has generated interest in the development of mitochondrial based TSPO-binding drugs for in vitro and in vivo analysis. Increased TSPO expression is observed in numerous pathologies such as cancer and inflammatory conditions of the central nervous system (CNS) that have been successfully exploited via protocols of positron emission tomography (PET) imaging. We endeavoured to dissect the molecular role of TSPO in mitochondrial cell biology and discovered a functional link with quality control mechanisms operated by selective autophagy. This review focuses on the current understanding of this pathway and focuses on the interplay with reactive oxygen species (ROS) and the voltage-dependent anion channel (VDAC), to which TSPO binds, in the regulation of cell mitophagy and hence homoeostasis of the mitochondrial network as a whole.
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Graham A, Allen AM. Mitochondrial function and regulation of macrophage sterol metabolism and inflammatory responses. World J Cardiol 2015; 7:277-286. [PMID: 26015858 PMCID: PMC4438467 DOI: 10.4330/wjc.v7.i5.277] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 02/25/2015] [Accepted: 03/18/2015] [Indexed: 02/06/2023] Open
Abstract
The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis. Macrophage generation of oxysterol activators of liver X receptors (LXRs), via sterol 27-hydroxylase, is regulated by the rate of flux of cholesterol to the inner mitochondrial membrane, via a complex of cholesterol trafficking proteins. Oxysterols are key signalling molecules, regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production, key features influencing the impact of these cells within atherosclerotic lesions. The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate, but may include steroidogenic acute regulatory protein and translocator protein. There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters (ABCA1, ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages. Thus, molecules which can sustain or improve mitochondrial structure, the function of the electron transport chain, or increase the activity of components of the protein complex involved in cholesterol transfer, may therefore have utility in limiting or regressing atheroma development, reducing the incidence of coronary heart disease and myocardial infarction.
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Abstract
PURPOSE OF REVIEW Noninvasive imaging of atherosclerotic plaques has substantially advanced over the past decade such that currently available imaging techniques allow for characterization of high-risk morphological features of the plaques and quantification of the biological activity within the atherosclerotic milieu. Vascular PET/CT imaging provides insights into the biological activity of atherosclerotic plaques and, in particular, plaque inflammation. Fluoro-deoxyglucose-PET/CT imaging is currently used to improve the understanding of atherosclerotic pathophysiology, facilitate the discovery of new treatments and improve clinical prognostication in humans. RECENT FINDINGS Several studies have evaluated the feasibility, validity and reproducibility of fluoro-deoxyglucose-PET/CT for imaging of atherosclerotic plaque inflammation. Fluoro-deoxyglucose-PET/CT imaging is demonstrated to have the potential to predict the efficacy of novel antiatherosclerotic therapeutics by using a relatively small sample size and within a relatively short time period in several multicenter trials. SUMMARY The currently feasible assessment of inflammation within the atherosclerotic plaques has been demonstrated to enhance assessment of clinical risk, provide a better understanding of therapeutic efficacy of novel drugs, and it may provide a window into inflammation within the coronary tree. Further technological advances in PET technology have the potential to catalyze further progress in imaging of atherosclerotic plaque biology.
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Affiliation(s)
- Hamed Emami
- aCardiac MR PET CT Program, Department of Imaging and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School bDivision of Cardiology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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