First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations

G-protein-coupled receptor 119 (GPR119) has emerged as
a promising
target for treating type 2 diabetes mellitus. Activating GPR119 improves
glucose homeostasis, while suppressing appetite and weight gain. Measuring
GPR119 levels in vivo could significantly advance
GPR119-based drug development strategies including target engagement,
occupancy, and distribution studies. To date, no positron emission
tomography (PET) ligands are available to image GPR119. In this paper,
we report the synthesis, radiolabeling, and preliminary biological
evaluations of a novel PET radiotracer [18F]KSS3 to image
GPR119. PET imaging will provide information on GPR119 changes with
diabetic glycemic loads and the efficacy of GPR119 agonists as antidiabetic
drugs. Our results demonstrate [18F]KSS3’s high
radiochemical purity, specific activity, cellular uptake, and in vivo and ex vivo uptake in pancreas,
liver, and gut regions, with high GPR119 expression. Cell pretreatment
with nonradioactive KSS3, rodent PET imaging, biodistribution, and
autoradiography studies showed significant blocking in the pancreas
showing [18F]KSS3’s high specificity.