Synthesis and biological evaluation of novel 18F-labeled 2,4-diaminopyrimidine derivatives for detection of ghrelin receptor in the brain.

ABSTRACT

The ghrelin receptor (GHSR) is known to regulate various physiological processes including appetite, food intake, and growth hormone release. Its expression is mainly observed in the brain, pancreas, stomach, and intestine. However, the functions of the receptor have not been fully elucidated. GHSR imaging with positron emission tomography (PET) is expected to further understanding of the functions and pathologies of the receptor. In this study, we newly designed and synthesized diaminopyrimidine derivatives ([18F]BPP-1 and [18F]BPP-2) and evaluated their utility as novel PET probes targeting GHSR. In in vitro competitive binding assays, the binding affinity of BPP-2 for GHSR (Ki = 274 nM) was comparable to that of the diaminopyimidine lead compound Abb8a (Ki = 109 nM). In a biodistribution study using normal mice, [18F]BPP-2 displayed low uptake in the brain and moderate uptake in the pancreas, but high radioactivity accumulation in bone was observed due to its defluorination in vivo. Taken together, although further improvement of the pharmacokinetics is needed, the diaminopyrimidine scaffold has potential for the development of useful GHSR-targeting PET probes.