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11C-Dihydrotetrabenazine B-Cell Imaging

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11C-Dihydrotetrabenazine B-Cell Imaging INVITED PERSPECTIVE 11C-Dihydrotetrabenazine b-Cell Imaging small fraction of b-cells (;2%) in the non-VMAT2 binding (and thus the total The prevalence of diabetes is dra- pancreas, requiring that tracers or con- pancreas binding) of 11C-dihydrotetrabe- matically high, and the acquired type trast agents have a high selectivity for nazine is also decreased in streptozotocin II form is particularly expected to fur- b-cells versus exocrine tissue. diabetic rats. In vitro autoradiography of ther increase considerably (from 6.6% A study that mapped gene ex- the human pancreas confirmed that of the world population [285 million pression showed that the vesicular dihydrotetrabenazine binding repre- people] in 2010 to 7.8% [439 million monoamine transporter 2 (VMAT2) is sents mainly nonspecific binding. people] in 2030) (1). Diabetes is caused expressed by b-cells but not by exo- Similar results have been published by a disrupted secretion of insulin and a crine pancreatic cells (5). 11C-dihydro- recently for 9-18F-fluoroethyl-(1)-dihy- subsequent increaseinplasmaglucose tetrabenazine, a PET tracer that had drotetrabenazine by Eriksson et al. (12), levels. Insulin is produced by the b-cells been developed to visualize VMAT2 who observed specific binding of the of the 1–2 million islets of Langerhans in the brain (6), was applied in PET tracer to isolated islet tissue but found in a pancreas. These islets represent studies of diabetes and showed less that specific islet binding did not suffi- only about 2%–3% of the pancreas cell pancreatic uptake in diabetic rats than ciently exceed nonspecific binding in mass, which consists mostly of exocrine in control rats (5) and a longitudinal the abundant exocrine pancreatic tissue b tissue. Autopsy studies have shown that decrease in the pancreatic standardized to allow -cell mass quantification. the relative b-cell volume is reduced uptake value (#65%) of spontaneous In the evaluation of future PET trac- b by more than 50% in diabetic subjects, diabetic rats (7). Encouraged by these ers of -cell mass (VMAT2), it will be results, researchers have synthesized important to include a thorough high- and are evaluating several 18Fderiva- resolution ex vivo and in vitro evalua- See page 1439 b tives of dihydrotetrabenazine (8,9). tion of -cell specificity focusing not b The preclinical results were par- only on high specific binding to -cells but also on low binding of the tracer or and animal models in which more than tially confirmed in clinical studies that 50% of the b-cell volume had been showed lower 11C-dihydrotetrabena- its metabolites to the abundant sur- rounding exocrine pancreatic tissue. destroyed have shown impaired glu- zine binding potentials in type 1 dia- cose homeostasis (2). betic patients than in control subjects. Thus, an important tool for diabetes Patients with longstanding type 1 dia- Guy M. Bormans Laboratory for Radiopharmaceutical research would be noninvasive in vivo betes are, however, expected to have a b b Sciences quantification of -cell mass, particu- near-total loss of -cell mass, whereas K.U. Leuven 11 larly longitudinal quantification for the observed C-dihydrotetrabenazine Leuven, Belgium monitoring new antidiabetic therapies. binding potential was still 86% of the b Research on imaging of -cell mass value in control subjects (10). It was REFERENCES has focused on various techniques hypothesized that the discrepancy be- 1. International Diabetes Federation Web site. (PET, SPECT, MRI, optical imaging) tween preclinical and clinical studies Diabetes and Impaired Glucose Tolerance: Global using, among others, peptides, antibod- was caused by modeling artifacts Burden—Prevalence and Projections, 2010 and 2030. Available at: http://www.diabetesatlas.org/ ies, manganese, annexin derivatives, introduced by using the kidney as a content/diabetes-and-impaired-glucose-tolerance. sulfonylureas, and 6-fluoro-L-dopa reference tissue, by the use of VMAT2 Accessed June 30, 2010. (3,4). The challenge of imaging b-cell expression in other cell types of the 2. Matveyenko AV, Butler PC. Relationship between ; beta-cell mass and diabetes onset. Diabetes Obes mass is the small dimensions ( 0.1- pancreas, and by species differences Metab. November 2008;(10 suppl 4):23–31. mm diameter) of the islets of Langer- in tracer kinetics or radiometabolite 3. Moore A. Advances in beta-cell imaging. Eur J hans, combined with the relatively accumulation. Radiol. 2009;70:254–257. 4. Lin M, Lubag A, McGuire MJ, et al. Advances in Using ex vivo autoradiography and molecular imaging of pancreatic beta cells. Front Received May 25, 2010; revision accepted Jun. in vitro tissue-binding competition Biosci. 2008;13:4558–4575. 3, 2010. studies, Fagerholm et al. now show 5. Simpson NR, Souza F, Witkowski P, et al. For correspondence or reprints contact: Guy M. Visualizing pancreatic beta-cell mass with [11C] Bormans, Laboratory for Radiopharmaceutical in this issue of The Journal of Nuclear DTBZ. Nucl Med Biol. 2006;33:855–864. Sciences, K.U. Leuven, Herestraat 49, Leuven Medicine that non-VMAT2 binding 6. Koeppe RA, Frey KA, Vander Borght TM, et al. B-3000, Belgium. 11 E-mail: [email protected] of 11C-dihydrotetrabenazine to exo- Kinetic evaluation of [ C]dihydrotetrabenazine by COPYRIGHT ª 2010 by the Society of Nuclear dynamic PET: measurement of vesicular monoamine Medicine, Inc. crine pancreas exceeds VMAT2 bind- transporter. J Cereb Blood Flow Metab. 1996;16: DOI: 10.2967/jnumed.110.077602 ing to b-cells (11). Interestingly, the 1288–1299. 11C-DIHYDROTETRABENAZINE b-CELL IMAGING • Bormans 1335 7. Souza F, Simpson N, Raffo A, et al. Longitudinal 9. Kung MP, Hou C, Lieberman BP, et al. In vivo 11. FagerholmV,Mikkola KK, IshizuT,et al.Assessment noninvasive PET-based beta cell mass estimates in imaging of beta-cell mass in rats using 18F-FP- of islet specificity of dihydrotetrabenazine radiotracer a spontaneous diabetes rat model. J Clin Invest. (1)-DTBZ: a potential PET ligand for studying binding in rat and human pancreas. JNuclMed. 2006;116:1506–1513. diabetes mellitus. J Nucl Med. 2008;49:1171–1176. 2010;51: 1439–1446. 8. Kung HF, Lieberman BP, Zhuang ZP, et al. In vivo 10. Goland R, Freeby M, Parsey R, et al. 11C- 12. Eriksson O, Jahan M, Johnstro¨m P, et al. In vivo imaging of vesicular monoamine transporter 2 in dihydrotetrabenazine PET of the pancreas in and in vitro characterization of [18F]-FE- pancreas using an 18F epoxide derivative of subjects with long-standing type 1 diabetes and (1)-DTBZ as a tracer for beta-cell mass. Nucl tetrabenazine. Nucl Med Biol. 2008;35:825–837. in healthy controls. J Nucl Med. 2009;50:382–389. Med Biol. 2010;37:357–363. 1336 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 51 • No. 9 • September 2010.
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