Synthesis and Characterization of Novel Radioiodinated Triazole-Pyrolidine Derivative to Detect Orexin 2 Receptor in the Brain.

It is generally accepted that the orexin 2 receptor (OX2R) plays a critical role in the arousal-promoting function, and in vivo imaging of OX2R is expected to contribute to elucidation of orexin systems and the development of drugs to treat sleep disorder. In this study, we newly synthesized and characterized a radioiodinated triazole-pyrolidine derivative ([125I]TPI) to detect OX2R in the brain. In vitro studies using OX1R or OX2R expression cells showed selective binding of [125I]TPI to OX2R. In addition, in vitro autoradiography using rat brain sections showed high accumulation of radioactivity in the OX2R expression region. However, [125I]TPI showed low brain uptake in normal mice. These results suggest that [125I]TPI has a fundamental character to detect OX2R in vitro, but further structural modification to improve brain pharmacokinetics is required to use it for in vivo detection of OX2R.

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.