Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Bioorg Med Chem Lett. 2021 Jul 1;43:128098. doi: 10.1016/j.bmcl.2021.128098. Epub 2021 May 10.
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.
虽然脑内的食欲素 1 型受体（orexin 1 receptor，OXR）被认为可以调节奖赏和摄食，但 OXR 的体内功能尚未完全阐明。用正电子发射断层扫描（positron emission tomography，PET）对 OXR 进行体内成像，可能有助于进一步了解 OXR 的分子细节。在本研究中，我们新设计并合成了一种苯并呋喃-2-甲酰胺（phenylbenzofuran-2-carboxamide，PBC）衍生物（[F]PBC-1），并评估了其作为脑内 OXR 靶向 PET 探针的应用潜力。细胞结合实验结果表明，[F]PBC-1 对 OXR 具有亲和力。在体外竞争抑制实验中，PBC-1 对 OXR（IC = 19.5 nM）表现出选择性结合亲和力，而对食欲素 2 型受体（orexin 2 receptor，OX2R，IC = 456.7 nM）则没有。此外，[F]PBC-1 在使用正常小鼠进行的生物分布研究中，具有足够的脑摄取量，可用于 PET 体内成像，但体内稳定性较差。这些结果表明，需要进一步修饰以改善药代动力学特性，但 PBC 支架具有开发脑内 OXR 靶向有用的 PET 探针的潜力。
