Visualizing pancreatic β-cell mass with [11C]DTBZ

Abstract

Abstractβ-Cell mass (BCM) influences the total amount of insulin secreted, varies by individual and by the degree of insulin resistance, and is affected by physiologic and pathologic conditions. The islets of Langerhans, however, appear to have a reserve capacity of insulin secretion and, overall, assessments of insulin and blood glucose levels remain poor measures of BCM, β-cell function and progression of diabetes. Thus, novel noninvasive determinations of BCM are needed to provide a quantitative endpoint for novel therapies of diabetes, islet regeneration and transplantation. Built on previous gene expression studies, we tested the hypothesis that the targeting of vesicular monoamine transporter 2 (VMAT2), which is expressed by β cells, with [ 11 C]dihydrotetrabenazine ([ 11 C]DTBZ), a radioligand specific for VMAT2, and the use of positron emission tomography (PET) can provide a measure of BCM. In this report, we demonstrate decreased radioligand uptake within the pancreas of Lewis rats with streptozotocininduced diabetes relative to their euglycemic historical controls. These studies suggest that quantitation of VMAT2 expression in β cells with the use of [ 11 C]DTBZ and PET represents a method for noninvasive longitudinal estimates of changes in BCM that may be useful in the study and treatment of diabetes.

Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands

“…Using multimodal imaging and inducible and selective beta-cell ablation, we demonstrate that the PET signal from radiolabeled VMAT2 ligands in the mouse pancreas does not correlate with beta-cell mass. Despite the loss of beta cells after DT administration, as monitored by BLI, mice with reduced beta-cell mass did not exhibit lower pancreatic retention of three different (24), may account for the reduced binding of [ 11 C]DTBZ after streptozotocin that was noted in previous reports (21,25).…”

“…Previous studies investigating radiolabeled DTBZ analogs for imaging the beta cell have led to contradictory conclusions. Studies in rodent models (21,22,25) and humans (23) have demonstrated a decrease in radiotracer retention in the pancreas of diabetics. However, other groups have found high radiotracer binding to the exocrine pancreas of rodents and humans (24,33,34) with reduced exocrine binding in the diabetic pancreas (24).…”

“…A radiolabeled ligand to VMAT2, dihydrotetrabenazine ([ 11 C]DTBZ) (19), has been extensively used in PET imaging of both human and rodent brains, revealing altered density of VMAT2 in diseased states such as Parkinson disease (20). [ 11 C]DTBZ has also been used for pancreatic islet imaging, showing reduced pancreatic uptake in rodent models of autoimmune and streptozotocin-induced diabetes (21,22). Imaging in humans has demonstrated lower pancreatic [ 11 C]DTBZ radioactivity in type 1 diabetics (23).…”

Radioisotopes in Drug Research and Development: Focus on Positron Emission Tomography

“…DTBZ can also be used to monitor BCM quantitatively for diabetes. PET tracers that have been used to quantify VMAT2 are [ 11 C]-dihydrotetrabenazine ([ 11 C]-DTBZ) ; Simpson et al, 2006;Murthy et al, 2008;Goland et al, 2009) (Kung et al, 2008(b)), which were shown to have high potency and selectivity for binding to VMAT2 in rats.…”

Pancreatic Imaging with 11C-Dihydrotetrabenazine PET: A Perspective

“…PET studies of VMAT2 pathophysiology are in their infancy; however, several important studies have been published by the group at Columbia University (19)(20)(21). In an investigation (19) with 11 C-DTBZ, they demonstrated decreased radioligand uptake in the pancreas of Lewis rats with streptozotocin-induced diabetes, compared with euglycemic historical controls.…”