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Joosten L, Boss M, Jansen T, Brom M, Buitinga M, Aarntzen E, Eriksson O, Johansson L, de Galan B, Gotthardt M. Molecular Imaging of Diabetes. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00041-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Evaluation of [ 68Ga]DO3A-VS-Cys 40-Exendin-4 as a PET Probe for Imaging Human Transplanted Islets in the Liver. Sci Rep 2019; 9:5705. [PMID: 30952975 PMCID: PMC6450933 DOI: 10.1038/s41598-019-42172-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 03/22/2019] [Indexed: 11/15/2022] Open
Abstract
[68Ga]DO3A-VS-Cys40-Exendin-4, a glucagon-like peptide 1 receptor agonist, was evaluated as a potential PET tracer for the quantitation of human islets transplanted to the liver. The short-lived PET radionuclide 68Ga, available on a regular basis from a 68Ge/68Ga generator, is an attractive choice. Human C-peptide was measured to evaluate human islet function post-transplantation and prior to microPET imaging. [68Ga]DO3A-VS-Cys40-Exendin-4 was radiosynthesized and evaluated for PET imaging of transplanted human islets in the liver of healthy NOD/SCID mice. The biodistribution of the tracer was evaluated to determine the uptake into various organs, and qPCR of liver samples was conducted to confirm engrafted islet numbers after PET imaging. Measurement of human C-peptide indicated that higher engrafted islet mass resulted in higher human C-peptide levels in post-transplantation. The microPET imaging yielded high resolution images of liver-engrafted islets and also showed significant retention in mouse livers at 8 weeks post-transplantation. Biodistribution studies in mice revealed that liver uptake of [68Ga]DO3A-VS-Cys40-Exendin-4 was approximately 6-fold higher in mice that received 1000 islet equivalent (IEQ) than in non-transplanted mice. qPCR analysis of insulin expression suggested that islet engraftment numbers were close to 1000 IEQ transplanted. In conclusion, human islets transplanted into the livers of mice exhibited significant uptake of [68Ga]DO3A-VS-Cys40-Exendin-4 compared to the livers of untreated mice; and imaging of the mice using PET showed the human islets clearly with high contrast against liver tissue, enabling accurate quantitation of islet mass. Further validation of [68Ga]DO3A-VS-Cys40-Exendin-4 as an islet imaging probe for future clinical application is ongoing.
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Korner J, Cline GW, Slifstein M, Barba P, Rayat GR, Febres G, Leibel RL, Maffei A, Harris PE. A role for foregut tyrosine metabolism in glucose tolerance. Mol Metab 2019; 23:37-50. [PMID: 30876866 PMCID: PMC6479665 DOI: 10.1016/j.molmet.2019.02.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 02/14/2019] [Accepted: 02/24/2019] [Indexed: 01/13/2023] Open
Abstract
Objective We hypothesized that DA and L-DOPA derived from nutritional tyrosine and the resultant observed postprandial plasma excursions of L-DOPA and DA might affect glucose tolerance via their ability to be taken-up by beta cells and inhibit glucose-stimulated β-cell insulin secretion. Methods To investigate a possible circuit between meal-stimulated 3,4-dihydroxy-L-phenylalanine (L-DOPA) and dopamine (DA) production in the GI tract and pancreatic β-cells, we: 1) mapped GI mucosal expression of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC); 2) measured L-DOPA and DA content of GI mucosal tissues following meal challenges with different L-tyrosine (TYR) content, 3) determined whether meal TYR content impacts plasma insulin and glucose excursions; and 4) characterized postprandial plasma excursions of L-DOPA and DA in response to meal tyrosine content in rodents and a population of bariatric surgery patients. Next, we characterized: 1) the metabolic transformation of TYR and L-DOPA into DA in vitro using purified islet tissue; 2) the metabolic transformation of orally administrated stable isotope labeled TYR into pancreatic DA, and 3) using a nuclear medicine technique, we studied endocrine beta cells in situ release and binding of DA in response to a glucose challenge. Results We demonstrate in rodents that intestinal content and circulatory concentrations L-DOPA and DA, plasma glucose and insulin are responsive to the tyrosine (TYR) content of a test meal. Intestinal expression of two enzymes, Tyrosine hydroxylase (TH) and Aromatic Amino acid Decarboxylase (AADC), essential to the transformation of TYR to DA was mapped and the metabolism of metabolism of TYR to DA was traced in human islets and a rodent beta cell line in vitro and from gut to the pancreas in vivo. Lastly, we show that β cells secrete and bind DA in situ in response to glucose stimulation. Conclusions We provide proof-of-principle evidence for the existence of a novel postprandial circuit of glucose homeostasis dependent on nutritional tyrosine. DA and L-DOPA derived from nutritional tyrosine may serve to defend against hypoglycemia via inhibition of glucose-stimulated β-cell insulin secretion as proposed by the anti-incretin hypothesis.
Nutritional tyrosine is metabolized to L DOPA and DA in the foregut. Postprandial L-DOPA and DA plasma concentrations rise in response to tyrosine. Oral stable isotope labeled tyrosine is found postprandially in the pancreas as DA. L-DOPA and DA are inhibitors of beta cell glucose-stimulated insulin secretion. Postprandial L-DOPA and DA excursions are muted in certain bariatric surgery patients.
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Affiliation(s)
- Judith Korner
- Department of Medicine and the Naomi Berrie Diabetes Center, Columbia University, College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Gary W Cline
- Yale Diabetes Research Center, Yale School of Medicine, New Haven, CT, 06520, USA
| | - Mark Slifstein
- Department of Psychiatry, Stony Brook University, Stony Brook, New York, NY, 11794, USA
| | - Pasquale Barba
- Institute of Genetics and Biophysics, Adriano Buzzati-Traverso, CNR, Naples, IT 80131, Italy
| | - Gina R Rayat
- Alberta Diabetes Institute, Ray Rajotte Surgical-Medical Research Institute, Department of Surgery, University of Alberta, Edmonton, AB, T6G 2E1 CA, Canada
| | - Gerardo Febres
- Department of Medicine and the Naomi Berrie Diabetes Center, Columbia University, College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Rudolph L Leibel
- Department of Medicine and the Naomi Berrie Diabetes Center, Columbia University, College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Antonella Maffei
- Department of Medicine and the Naomi Berrie Diabetes Center, Columbia University, College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Paul E Harris
- Department of Medicine and the Naomi Berrie Diabetes Center, Columbia University, College of Physicians and Surgeons, New York, NY, 10032, USA.
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Abstract
The clinical onset of type 1 diabetes is characterized by the destruction of the insulin-producing β cells of the pancreas and is caused by autoantigen-induced inflammation (insulitis) of the islets of Langerhans. The current standard of care for type 1 diabetes mellitus patients allows for management of the disease with exogenous insulin, but patients eventually succumb to many chronic complications such as limb amputation, blindness, and kidney failure. New therapeutic approaches now on the horizon are looking beyond glycemic management and are evaluating new strategies from protecting and regenerating endogenous islets to treating the underlying autoimmunity through selective modulation of key immune cell populations. Currently, there are no effective treatments for the autoimmunity that causes the disease, and strategies that aim to delay or prevent the onset of the disease will play an important role in the future of diabetes research. In this review, we summarize many of the key efforts underway that utilize molecular approaches to selectively modulate this disease and look at new therapeutic paradigms that can transform clinical treatment.
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Affiliation(s)
- Daniel Sheehy
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States
| | - Sean Quinnell
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States
| | - Arturo J. Vegas
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States
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5
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Wei W, Ehlerding EB, Lan X, Luo QY, Cai W. Molecular imaging of β-cells: diabetes and beyond. Adv Drug Deliv Rev 2019; 139:16-31. [PMID: 31378283 DOI: 10.1016/j.addr.2018.06.022] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 04/27/2018] [Accepted: 06/26/2018] [Indexed: 02/09/2023]
Abstract
Since diabetes is becoming a global epidemic, there is a great need to develop early β-cell specific diagnostic techniques for this disorder. There are two types of diabetes (i.e., type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)). In T1DM, the destruction of pancreatic β-cells leads to reduced insulin production or even absolute insulin deficiency, which consequently results in hyperglycemia. Actually, a central issue in the pathophysiology of all types of diabetes is the relative reduction of β-cell mass (BCM) and/or impairment of the function of individual β-cells. In the past two decades, scientists have been trying to develop imaging techniques for noninvasive measurement of the viability and mass of pancreatic β-cells. Despite intense scientific efforts, only two tracers for positron emission tomography (PET) and one contrast agent for magnetic resonance (MR) imaging are currently under clinical evaluation. β-cell specific imaging probes may also allow us to precisely and specifically visualize transplanted β-cells and to improve transplantation outcomes, as transplantation of pancreatic islets has shown promise in treating T1DM. In addition, some of these probes can be applied to the preoperative detection of hidden insulinomas as well. In the present review, we primarily summarize potential tracers under development for imaging β-cells with a focus on tracers for PET, SPECT, MRI, and optical imaging. We will discuss the advantages and limitations of the various imaging probes and extend an outlook on future developments in the field.
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Bini J, Naganawa M, Nabulsi N, Huang Y, Ropchan J, Lim K, Najafzadeh S, Herold KC, Cline GW, Carson RE. Evaluation of PET Brain Radioligands for Imaging Pancreatic β-Cell Mass: Potential Utility of 11C-(+)-PHNO. J Nucl Med 2018; 59:1249-1254. [PMID: 29371405 DOI: 10.2967/jnumed.117.197285] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 12/07/2017] [Indexed: 12/21/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is characterized by a loss of β-cells in the islets of Langerhans of the pancreas and subsequent deficient insulin secretion in response to hyperglycemia. Development of an in vivo test to measure β-cell mass (BCM) would greatly enhance the ability to track diabetes therapies. β-cells and neurologic tissues have common cellular receptors and transporters, therefore, we screened brain radioligands for their ability to identify β-cells. Methods: We examined a β-cell gene atlas for endocrine pancreas receptor targets and cross-referenced these targets with brain radioligands that were available at our institution. Twelve healthy control subjects and 2 T1DM subjects underwent dynamic PET/CT scans with 6 tracers. Results: The D2/D3 receptor agonist radioligand 11C-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO) was the only radioligand to demonstrate sustained uptake in the pancreas with high contrast versus abdominal organs such as the kidneys, liver, and spleen, based on the first 30 min of data. Mean SUV from 20 to 30 min demonstrated high uptake of 11C-(+)-PHNO in healthy controls (SUV, 13.8) with a 71% reduction in a T1DM subject with undetectable levels of C-peptide (SUV, 4.0) and a 20% reduction in a T1DM subject with fasting C-peptide level of 0.38 ng/mL (SUV, 11.0). SUV in abdominal organs outside the pancreas did not show measurable differences between the control and T1DM subjects, suggesting that the changes in SUV of 11C-(+)-PHNO may be specific to changes in the pancreas between healthy controls and T1DM subjects. When D3 and D2 antagonists were used in nonhuman primates, specific pancreatic binding (SUVR-1) of 11C-PHNO was reduced by 57% and 38%, respectively. Conclusion:11C-(+)-PHNO is a potential marker of BCM, with 2:1 binding of D3 receptors over D2 receptors. Further in vitro and in vivo studies to establish D2/D3 receptor specificity to β-cells is warranted to characterize 11C-(+)-PHNO as a candidate for clinical measurement of BCM in healthy control and diabetic subjects.
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Affiliation(s)
- Jason Bini
- PET Center, Yale University School of Medicine, New Haven, CT .,Department of Biomedical Engineering, Yale University, New Haven, CT; and
| | - Mika Naganawa
- PET Center, Yale University School of Medicine, New Haven, CT
| | - Nabeel Nabulsi
- PET Center, Yale University School of Medicine, New Haven, CT
| | - Yiyun Huang
- PET Center, Yale University School of Medicine, New Haven, CT
| | - Jim Ropchan
- PET Center, Yale University School of Medicine, New Haven, CT
| | - Keunpoong Lim
- PET Center, Yale University School of Medicine, New Haven, CT
| | | | - Kevan C Herold
- Department of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Gary W Cline
- Department of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Richard E Carson
- PET Center, Yale University School of Medicine, New Haven, CT.,Department of Biomedical Engineering, Yale University, New Haven, CT; and
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Willekens SMA, van der Kroon I, Bos D, Joosten L, Frielink C, Boerman OC, Brom M, Gotthardt M. Quantitative and longitudinal imaging of intramuscular transplanted islets of Langerhans with SPECT using [ 123 I]IBZM. Diabetes Obes Metab 2017; 19:604-608. [PMID: 27987245 DOI: 10.1111/dom.12857] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 11/30/2016] [Accepted: 12/12/2016] [Indexed: 11/30/2022]
Abstract
A non-invasive imaging method to monitor islet grafts could provide novel and improved insight into the fate of transplanted islets and, potentially, monitor the effect of therapeutic interventions. Therefore, such an imaging method could help improve long-term transplantation outcome. Here, we investigated the use of [ 123 I]IBZM for insulin positive graft volume quantification and longitudinal graft monitoring. SPECT images were acquired 6 weeks after islet transplantation in the calf muscle of rats. For longitudinal graft analysis, rats were monitored by SPECT for 10 weeks. After animals were euthanized, graft containing muscles were dissected for ex vivo analysis and insulin-positive graft volume determination. Six weeks after transplantation, a clear signal was observed in all grafts by SPECT imaging. Moreover, the intensity of the SPECT signal correlated linearly with insulin-positive graft volume, as determined histologically. Longitudinal graft follow-up showed a clear SPECT signal of the transplant from 3 until 10 weeks after transplantation. In this study, we demonstrate for the first time the successful application of a radiotracer, [ 123 I]IBZM, for non-invasive, in vivo graft volume quantification and longitudinal graft monitoring.
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Affiliation(s)
- Stefanie M A Willekens
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Inge van der Kroon
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Desirée Bos
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lieke Joosten
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Cathelijne Frielink
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Otto C Boerman
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Maarten Brom
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Martin Gotthardt
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
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Jodal A, Schibli R, Béhé M. Targets and probes for non-invasive imaging of β-cells. Eur J Nucl Med Mol Imaging 2016; 44:712-727. [PMID: 28025655 PMCID: PMC5323463 DOI: 10.1007/s00259-016-3592-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 12/01/2016] [Indexed: 12/16/2022]
Abstract
β-cells, located in the islets of the pancreas, are responsible for production and secretion of insulin and play a crucial role in blood sugar regulation. Pathologic β-cells often cause serious medical conditions affecting blood glucose level, which severely impact life quality and are life-threatening if untreated. With 347 million patients, diabetes is one of the most prevalent diseases, and will continue to be one of the largest socioeconomic challenges in the future. The diagnosis still relies mainly on indirect methods like blood sugar measurements. A non-invasive diagnostic imaging modality would allow direct evaluation of β-cell mass and would be a huge step towards personalized medicine. Hyperinsulinism is another serious condition caused by β-cells that excessively secrete insulin, like for instance β-cell hyperplasia and insulinomas. Treatment options with drugs are normally not curative, whereas curative procedures usually consist of the resection of affected regions for which, however, an exact localization of the foci is necessary. In this review, we describe potential tracers under development for targeting β-cells with focus on radiotracers for PET and SPECT imaging, which allow the non-invasive visualization of β-cells. We discuss either the advantages or limitations for the various tracers and modalities. This article concludes with an outlook on future developments and discuss the potential of new imaging probes including dual probes that utilize functionalities for both a radioactive and optical moiety as well as for theranostic applications.
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Affiliation(s)
- Andreas Jodal
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen, Switzerland
| | - Roger Schibli
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen, Switzerland.,Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Martin Béhé
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen, Switzerland.
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Baranwal A, Mirbolooki MR, Mukherjee J. Initial Assessment of β3-Adrenoceptor-Activated Brown Adipose Tissue in Streptozotocin-Induced Type 1 Diabetes Rodent Model Using [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. Mol Imaging 2016; 14:22-33. [PMID: 26637263 DOI: 10.2310/7290.2015.00028] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Metabolic activity of brown adipose tissue (BAT) is activated by β3-adrenoceptor agonists and norepinephrine transporter (NET) blockers and is measurable using [(18)F]fluorodeoxyglucose ([(18)F]FDG) positron emission tomography/computed tomography (PET/CT) in rats. Using the streptozotocin (STZ)-treated rat model of type 1 diabetes mellitus (T1DM), we investigated BAT activity in this rat model under fasting and nonfasting conditions using [(18)F]FDG PET/CT. Drugs that enhance BAT activity may have a potential for therapeutic development in lowering blood sugar in insulin-resistant diabetes. Rats were rendered diabetic by administration of STZ and confirmed by glucose measures. [(18)F]FDG was injected in the rats (fasted or nonfasted) pretreated with either saline or β3-adrenoceptor agonist CL316,243 or the NET blocker atomoxetine for PET/CT scans. [(18)F]FDG metabolic activity was computed as standard uptake values (SUVs) in interscapular brown adipose tissue (IBAT) and compared across the different drug treatment conditions. Blood glucose levels > 500 mg/dL were established for the STZ-treated diabetic rats. Under fasting conditions, average uptake of [(18)F]FDG in the IBAT of STZ-treated diabetic rats was approximately 70% lower compared to that of normal rats. Both CL316,243 and atomoxetine activated IBAT in normal rats had an SUV > 5, whereas activation in STZ-treated rats was significantly lower. The agonist CL316,243 activated IBAT up to threefold compared to saline in the fasted STZ-treated rat. In the nonfasted rat, the IBAT activation was up by twofold by CL316243. Atomoxetine had a greater effect on lowering blood sugar levels compared to CL316,243 in the nonfasted rats. A significant reduction in metabolic activity was observed in the STZ-treated diabetic rodent model. Increased IBAT activity in the STZ-treated diabetic rat under nonfasted conditions using the β3-adrenoceptor agonist CL316,243 suggests a potential role of BAT in modulating blood sugar levels. Further studies are needed to evaluate the therapeutic role of β3-adrenoceptor agonists in insulin-resistant T1DM.
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Miceli V, Meli V, Blanchard-Desce M, Bsaibess T, Pampalone M, Conaldi PG, Caltagirone C, Obiols-Rabasa M, Schmidt J, Talmon Y, Casu A, Murgia S. In vitro imaging of β-cells using fluorescent cubic bicontinuous liquid crystalline nanoparticles. RSC Adv 2016; 6:62119-62127. [DOI: 10.1039/c6ra09616f] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Imaging of rat pancreatic β-cells using cubic bicontinuous liquid crystalline nanoparticles loaded with the TB139 fluorescent dye.
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Barsanti C, Lenzarini F, Kusmic C. Diagnostic and prognostic utility of non-invasive imaging in diabetes management. World J Diabetes 2015; 6:792-806. [PMID: 26131322 PMCID: PMC4478576 DOI: 10.4239/wjd.v6.i6.792] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 12/23/2014] [Accepted: 04/14/2015] [Indexed: 02/05/2023] Open
Abstract
Medical imaging technologies are acquiring an increasing relevance to assist clinicians in diagnosis and to guide management and therapeutic treatment of patients, thanks to their non invasive and high resolution properties. Computed tomography, magnetic resonance imaging, and ultrasonography are the most used imaging modalities to provide detailed morphological reconstructions of tissues and organs. In addition, the use of contrast dyes or radionuclide-labeled tracers permits to get functional and quantitative information about tissue physiology and metabolism in normal and disease state. In recent years, the development of multimodal and hydrid imaging techniques is coming to be the new frontier of medical imaging for the possibility to overcome limitations of single modalities and to obtain physiological and pathophysiological measurements within an accurate anatomical framework. Moreover, the employment of molecular probes, such as ligands or antibodies, allows a selective in vivo targeting of biomolecules involved in specific cellular processes, so expanding the potentialities of imaging techniques for clinical and research applications. This review is aimed to give a survey of characteristics of main diagnostic non-invasive imaging techniques. Current clinical appliances and future perspectives of imaging in the diagnostic and prognostic assessment of diabetic complications affecting different organ systems will be particularly addressed.
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Kaur J, Khararjian A, Coleman RA, Constantinescu CC, Pan ML, Mukherjee J. Spinal cord dopamine D2/D3 receptors: in vivo and ex vivo imaging in the rat using (18)F/(11)C-fallypride. Nucl Med Biol 2014; 41:841-7. [PMID: 25199843 DOI: 10.1016/j.nucmedbio.2014.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Revised: 07/31/2014] [Accepted: 08/03/2014] [Indexed: 10/24/2022]
Abstract
OBJECTIVES The spinal cord is known to be innervated with dopaminergic cells with catecholaminergic projections arising from the medulla and pons and dopaminergic transmission in the spinal cord is vital for sensory and motor function. Our goal was to evaluate and compare the imaging capability of dopamine D2/D3 receptors in the rat spinal cord using PET ligands (18)F-fallypride and (11)C-fallypride. METHODS Male Sprague-Dawley rats were used in all in vitro and in vivo studies. Spinal cord and brain sections were used for in vitro autoradiography and ex vivo autoradiography. For in vivo studies animals received a (18)F-fallypride scan or a (11)C-fallypride PET scan. The spinal cord and the brain were then harvested, flash-frozen and imaged ex vivo. For in vivo analysis Logan plots with cerebellum as a reference was used to evaluate binding potentials (BP). Tissue ratios were used for ex vivo analysis. Drug effects were evaluated using clozapine, haloperidol and dopamine were evaluated on spinal cord sections in vitro. RESULTS In vitro studies showed (18)F-fallypride binding to superficial dorsal horn (SDH), dorsal horn (DH), ventral horn (VH) and the pars centralis (PC). In the cervical section, the greatest amount of binding appeared to be in the SDH. Ex vivo studies showed approximately 6% of (18)F-fallypride in SDH compared to that observed in the striatum. In vivo analysis of both (18)F-fallypride and (11)C-fallypride in the spinal cord were comparable to that in the extrastriatal regions. Haloperidol and clozapine displaced more than 75% of the (18)F-fallypride in spinal cord sections. CONCLUSIONS Our studies showed (18)F-fallypride and (11)C-fallypride binding in the spinal cord in vitro and in vivo. The binding pattern correlates well with the known distribution of dopamine D2/D3 receptors in the spinal cord.
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Affiliation(s)
- Jasmeet Kaur
- Preclinical Imaging, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697
| | - Armen Khararjian
- Preclinical Imaging, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697
| | - Robert A Coleman
- Preclinical Imaging, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697
| | - Cristian C Constantinescu
- Preclinical Imaging, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697
| | - Min-Liang Pan
- Preclinical Imaging, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697
| | - Jogeshwar Mukherjee
- Preclinical Imaging, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697.
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