Synthesis and biological evaluation of novel 18F-labeled phenylbenzofuran-2-carboxamide derivative for detection of orexin 1 receptor in the brain
Synthesis and biological evaluation of novel 18F-labeled phenylbenzofuran-2-carboxamide derivative for detection of orexin 1 receptor in the brain
复制标题
用于检测大脑中食欲素1受体的新型18F标记苯基苯并呋喃-2-甲酰胺衍生物的合成和生物学评价
DOI：
10.1016/j.bmcl.2021.128098
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Ono Masahiro
中科院分区：
文献类型：
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作者：
Watanabe Hiroyuki;Idoko Yuki;Iikuni Shimpei;Ide Takuji;Shimizu Yoichi;Nakamoto Yuji;Ono Masahiro
虽然大脑中的食欲素1受体（OX1R）被认为调节奖赏和摄食，但其体内功能尚未完全阐明。利用正电子发射断层扫描（PET）对OX1R进行体内成像，可能有助于进一步了解OX1R的分子细节。在这项研究中，我们新设计并合成了一种苯基苯并呋喃-2-羧酸酰胺（PBC）衍生物（[18F]PBC-1），并评估了其作为靶向脑内OX1R的PET探针的实用性。细胞结合实验结果表明[18F]PBC-1对OX1R具有亲和力。在anin体外竞争抑制实验中，PBC-1对OX1R （IC50= 19.5 nM）对orexin 2受体（IC50= 456.7 nM）具有选择性结合亲和力。此外，[18F]在正常小鼠的生物分布研究中，PBC-1在PET体内成像中显示出足够的脑摄取，但观察到体内不稳定性。这些结果表明，需要进一步修改以改善药代动力学，但PBC支架具有开发针对脑中OX1R的有用PET探针的潜力。
Although the orexin 1 receptor (OX1R) in the brain is considered to regulate reward and feeding, thein vivofunction of OX1R has not been fully elucidated.In vivoimaging 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 anin vitrocompetitive 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 forin vivoimaging with PET in a biodistribution study using normal mice, butin vivoinstability 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.