Radiosynthesis and in Vivo Evaluation of Neuropeptide Y5 Receptor (NPY₅R) PET Tracers

Neuropeptide Y receptor type 5 (NPY₅R) is a G-protein coupled receptor (GPCR) that belongs to the subfamily of neuropeptide receptors (NPYR) that mediate the action of endogenous neuropeptide Y (NPY). Animal models and preclinical studies indicate a role for NPY₅R in the pathophysiology of depression, anxiety, and obesity and as a target of potential therapeutic drugs. To better understand the pathophysiological involvement of NPY₅R, and to measure target occupancy by potential therapeutic drugs, it would be advantageous to measure NPY₅R binding in vivo by positron emission tomography (PET). Four potent and selective NPY₅R antagonists were radiolabeled via nucleophilic aromatic substitution reactions with [¹⁸F]fluoride. Of the four radioligands investigated, PET studies in anesthetized baboons showed that [¹⁸F]LuAE00654 ([¹⁸F]N-[trans-4-({[4-(2-fluoropyridin-3-yl)thiazol-2-yl]amino}methyl)cyclohexyl]propane-2-sulfonamide) penetrates blood brain barrier (BBB) and a small amount is retained in the brain. Slow metabolism of [¹⁸F]LuAE00654 was observed in baboon plasma. Blocking studies with a specific NPY₅R antagonist demonstrated up to 60% displacement of radioactivity in striatum, the brain region with highest NPY₅R binding. Our studies suggest that [¹⁸F]LuAE00654 can be a potential PET radiotracer for the quantification and occupancy studies of NPY₅R drug candidates.