In vivo imaging of vesicular monoamine transporter 2 in pancreas using an 18F epoxide derivative of tetrabenazine

Abstract

Objectives-Development of imaging agents for pancreatic beta cell mass may provide tools for studying insulin-secreting beta cells and their relationship with diabetes mellitus. In this paper a new imaging agent, [ 18 F](+)-2-oxiranyl-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline [ 18 F](+)4, which displays properties targeting vesicular monoamine transporter 2 (VMAT2) binding sites of beta cells in the pancreas, was evaluated as a PET (positron emission tomography) agent for estimating beta cell mass in vivo. The hydrolyzable epoxide group of (+)4 may provide a mechanism for shifting biodistribution from liver to kidney thus, reducing the background signal.Methods-Both 18 F and 19 F labeled (+) and (−) isomers of 4 were synthesized and evaluated. Organ distribution was carried out in normal rats. Uptake of [ 18 F](+)4 in pancreas of normal rats was measured and correlated with blocking studies using competing drugs, (+)dihydrotetrabenazine, (+)-DTBZ or 9-fluoropropyl-(+)dihydro tetrabenazine (FP-(+)-DTBZ, (+)2).Results-In vitro binding study of VMAT2 using rat brain striatum showed a K i value of 0.08 and 0.15 nM for the (+)4 and (±)4, respectively. The in vivo biodistribution of [ 18 F](+)4 in rats showed the highest uptake in the pancreas (2.68 %ID/g at 60 min post-injection). In vivo competition experiments with cold FP-(+)-DTBZ, (+)2, (3.5 mg/kg, 5 min iv pretreatment) led to a significant reduction of pancreas uptake (85 % blockade at 60 min). The inactive isomer [ 18 F](−)4 showed significantly lower pancreas uptake (0.22 %ID/g at 30 min post-injection). Animal PET imaging studies of [ 18 F](+)4 in normal rats demonstrated an avid pancreatic uptake in rats. Conclusion-The preliminary results suggest that the epoxide, [ 18 F](+)4, is highly selective in binding to VMAT2 and it has an excellent uptake in the pancreas of rats. The liver uptake was significantly reduced through the use of the epoxide group. Therefore, it may be potentially useful for imaging beta cell mass in the pancreas.

Assessment of Islet Specificity of Dihydrotetrabenazine Radiotracer Binding in Rat Pancreas and Human Pancreas

“…Similar levels of pancreatic uptake of 3 H-DTBZ and 11 C-DTBZ as well as DTBZ derivatives were reported previously (13,14,22,23). In those studies, the islet and VMAT2 specificity of the accumulated radioactivity was not assessed directly.…”

“…A higher affinity for VMAT2 could improve the labeling of pancreatic islets. However, because 11 C-DTBZ and its derivatives displayed similarly high levels of pancreatic uptake when injected into rats (22,23), the derivatives are likely to exhibit the same type of nonspecific pancreatic binding as the parent compound.…”

In Vivo Imaging of Endogenous Pancreatic β-Cell Mass in Healthy and Type 1 Diabetic Subjects Using 18F-Fluoropropyl-Dihydrotetrabenazine and PET

“…Strategies for imaging BCM by positron emission tomography (PET) and single photon emission tomography (SPECT) using radiotracers targeted to β-cell-specific binding sites have been explored (1–9). Of the radioligands identified to date, only those targeting vesicular monoamine transporter type 2 (VMAT2) have warranted phase 1 clinical evaluation for quantitative imaging of BCM in humans (5–9). …”

11C-Dihydrotetrabenazine β-Cell Imaging

“…11 C-dihydrotetrabenazine, a PET tracer that had been developed to visualize VMAT2 in the brain (6), was applied in PET studies of diabetes and showed less pancreatic uptake in diabetic rats than in control rats (5) and a longitudinal decrease in the pancreatic standardized uptake value (#65%) of spontaneous diabetic rats (7). Encouraged by these results, researchers have synthesized and are evaluating several 18 F derivatives of dihydrotetrabenazine (8,9).…”