Evaluation of pancreatic VMAT2 binding with active and inactive enantiomers of F-FP-DTBZ in baboons.

INTRODUCTION

F-Fluoropropyl-(+)-dihydrotetrabenazine (F-FP-(+)-DTBZ) is a vesicular monoamine transporter type 2 (VMAT2) radiotracer for positron emission tomography (PET) imaging to quantify human β-cell mass. Renal cortex and spleen have been suggested as reference regions, however, little is known about F-FP-(+)-DTBZ binding in these regions including the fraction of radiometabolite. We compared the kinetics of F-FP-(+)-DTBZ and its inactive enantiomer F-FP-(-)-DTBZ in baboons, estimated the non-displaceable binding (V) of the tracers, and used ex vivo studies to measure radiometabolite fractions.

METHODS

PET scans were conducted for up to 4h with (+) and (-) enantiomers. Displacement experiments using unlabeled (+) and (-) enantiomers of FP-DTBZ and fluvoxamine (to evaluate sigma-1 receptor binding) were performed. SUV curves were used to calculate displacement values in the pancreas, renal cortex, and spleen. Distribution volumes (V) were computed, and three approaches for calculation of V were compared: (1) F-FP-(+)-DTBZ reference V, (2) F-FP-(-)-DTBZ pancreatic V, and (3) a scaled F-FP-(+)-DTBZ reference V values. Ex vivo study was conducted to measure radiometabolite fraction in homogenized tissue samples from baboons at 90min post-injection.

RESULTS

Spleen uptake was lowest for both tracers. Highest uptake was in the pancreas with F-FP-(+)-DTBZ and renal cortex with F-FP-(-)-DTBZ. Substantial displacement effect was observed only with unlabeled FP-(+)-DTBZ in the F-FP-(+)-DTBZ studies. Radiometabolite fraction was higher in the renal cortex than the spleen. Approaches (1) and (3) with spleen to estimate V provided lowest inter-subject variability of BP.

CONCLUSIONS

V differences among organs and between enantiomers indicated that scaling of reference region values is needed for quantification of VMAT2 binding in the pancreas with F-FP-(+)-DTBZ. Since the kidney PET signal has greater partial volume averaging and more radiometabolites, the spleen was considered a more practical candidate for use as a scaled-reference region in the quantification of F-FP-(+)-DTBZ in the pancreas.