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

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