Synthesis and biological evaluation of novel F-labeled phenylbenzofuran-2-carboxamide derivative for detection of orexin 1 receptor in the brain.

Although the orexin 1 receptor (OXR) in the brain is considered to regulate reward and feeding, the in vivo function of OXR has not been fully elucidated. In vivo imaging of OXR with positron emission tomography (PET) may be useful to further understand the molecular details of OXR. In this study, we newly designed and synthesized a phenylbenzofuran-2-carboxamide (PBC) derivative ([F]PBC-1) and evaluated its utility as a PET probe targeting OXR in the brain. The results of cell binding assays suggested that [F]PBC-1 has affinity for OXR. In an in vitro competitive inhibition assay, PBC-1 showed selective binding affinity for OXR (IC = 19.5 nM) over orexin 2 receptor (IC = 456.7 nM). Furthermore, [F]PBC-1 displayed sufficient brain uptake for in vivo imaging with PET in a biodistribution study using normal mice, but in vivo instability was observed. These results suggest that further modifications for improvement of the pharmacokinetics are needed, but the PBC scaffold has potential for the development of useful PET probes targeting OXR in the brain.