Assessment of islet specificity of dihydrotetrabenazine radiotracer binding in rat pancreas and human pancreas

Abstract

Vesicular monoamine transporter 2 (VMAT2) is a putative molecular target for the quantitative imaging of pancreatic β-cell mass by PET. The VMAT2 PET tracer 11C-dihydrotetrabenazine (11C-DTBZ) exhibits high pancreatic uptake that is reduced in type 1 diabetes. The aim of this study was to assess the islet and VMAT2 specificity of DTBZ binding in the pancreas. Methods: The biodistribution of 11C-DTBZ in rats was determined 10 and 60 min after injection. The localization of DTBZ radioactivity in rat and human pancreatic tissue sections was investigated by autoradiography. Saturation and competition binding assays were performed with 3H-DTBZ and sections of rat pancreatic and control tissues. The binding of 11C-DTBZ in pancreatic sections from rats with streptozotocin-induced diabetes was compared with that in control rats. Results: The values for the pancreatic uptake of 11C-DTBZ (percentage injected dose per gram of tissue) were 3.0 at 10 min and 2.7 at 60 min. At 10 min, pancreatic radioactivity was heterogeneously distributed, with higher levels toward the head of the pancreas (head-to-tail ratio, 1.7). No such gradient was observed in pancreatic sections incubated with 11C-DTBZ and 3H-DTBZ in vitro. In rats, 11C-DTBZ and 3H-DTBZ binding in pancreatic islets did not exceed binding in the exocrine pancreas. Saturable 3H-DTBZ binding was observed in the rat brain striatum (dissociation constant [Kd], 1.3 nM) and the bovine adrenal medulla (Kd, 3.3 nM), whereas in the rat pancreas, 3H-DTBZ binding was nonsaturable. Competition binding with 3H-DTBZ and VMAT2 antagonists also indicated that DTBZ binding in the rat pancreas was nonspecific and did not represent binding to VMAT2. Nonspecific pancreatic 11C-DTBZ binding was lower in rats with streptozotocin-induced diabetes than in control rats. In sections of human pancreas, a subset of pancreatic islets were weakly but VMAT2-specifically labeled with 3H-DTBZ. Conclusion: The results showed that the pancreatic uptake of 11C-DTBZ is mainly due to nonspecific binding in the exocrine pancreas and suggested that the reduction in pancreatic 11C-DTBZ binding observed in type 1 diabetes is not specific for the loss of β-cell mass. COPYRIGHT © 2010 by the Society of Nuclear Medicine, Inc.