Synthesis and biological evaluation of novel 18F-labeled phenylbenzofuran-2-carboxamide derivative for detection of orexin 1 receptor in the brain.

Although the orexin 1 receptor (OX1R) in the brain is considered to regulate reward and feeding, the in vivo function of OX1R has not been fully elucidated. In vivo imaging of OX1R with positron emission tomography (PET) may be useful to further understand the molecular details of OX1R. In this study, we newly designed and synthesized a phenylbenzofuran-2-carboxamide (PBC) derivative ([18F]PBC-1) and evaluated its utility as a PET probe targeting OX1R in the brain. The results of cell binding assays suggested that [18F]PBC-1 has affinity for OX1R. In an in vitro competitive inhibition assay, PBC-1 showed selective binding affinity for OX1R (IC50 = 19.5 nM) over orexin 2 receptor (IC50 = 456.7 nM). Furthermore, [18F]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 OX1R in the brain.

Synthesis and biological evaluation of F-18 labeled tetrahydroisoquinoline derivatives targeting orexin 1 receptor.

Orexin 1 receptor (OX1R) is thought to be involved in various body functions, including arousal maintenance and emotional control, but the full details of its function remain unknown. OX1R imaging with positron emission tomography (PET) would be useful in elucidating the orexin system including OX1R, but no PET probes targeting OX1R have been reported. We, therefore, designed and synthesized tetrahydroisoquinoline (THIQ) derivatives as novel PET probes targeting OX1R, and evaluated their utility. In an in vitro competitive binding assay, THIQ-1 and THIQ-2 showed significantly higher binding to OX1R (IC50 = 30 and 31 nM, respectively) than OX2R (IC50 = 160 and 332 nM, respectively). These features were also observed in a cell binding assay using [18F]THIQ-1 and [18F]THIQ-2, demonstrating their OX1R-specific binding property in vitro. In a biodistribution study using normal mice, the brain uptake of [18F]THIQ-1 was higher than that of [18F]THIQ-2, but further improvement is required for in vivo imaging with PET. Taken together, [18F]THIQ-1 and [18F]THIQ-2 have the potential to become useful imaging probes for PET targeting the OX1R, but require additional structural changes to improve their brain uptake.