Acta Pharmaceutica Sinica B ( IF 14.5 ) Pub Date : 2021-09-04 , DOI: 10.1016/j.apsb.2021.08.029 Ying Zhang 1 , Tao Wang 1 , Xiaojun Zhang 2 , Winnie Deuther-Conrad 3 , Hualong Fu 1 , Mengchao Cui 1 , Jinming Zhang 2 , Peter Brust 3, 4 , Yiyun Huang 5 , Hongmei Jia 1
We have discovered and synthesized a series of indole-based derivatives as novel sigma-2 (σ2) receptor ligands. Two ligands with high σ2 receptor affinity and subtype selectivity were then radiolabeled with F-18 in good radiochemical yields and purities, and evaluated in rodents. In biodistribution studies in male ICR mice, radioligand [18F]9, or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]fluoroethoxy)-1H-indole, was found to display high brain uptake and high brain-to-blood ratio. Pretreatment of animals with the selective σ2 receptor ligand CM398 led to significant reductions in both brain uptake (29%–54%) and brain-to-blood ratio (60%–88%) of the radioligand in a dose-dependent manner, indicating high and saturable specific binding of [18F]9 to σ2 receptors in the brain. Further, ex vivo autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of [18F]9 in the brain that is consistent with the distribution pattern of σ2 receptors. Dynamic positron emission tomography imaging confirmed regionally distinct distribution and high levels of specific binding for [18F]9 in the rat brain, along with appropriate tissue kinetics. Taken together, results from our current study indicated the novel radioligand [18F]9 as the first highly specific and promising imaging agent for σ2 receptors in the brain.
中文翻译:
用于 sigma-2 受体神经成像的脑穿透性 18F 标记放射性配体的发现和开发
我们已经发现并合成了一系列基于吲哚的衍生物作为新型 sigma-2 ( σ 2 ) 受体配体。然后用 F-18 以良好的放射化学产率和纯度对两种具有高σ 2受体亲和力和亚型选择性的配体进行放射性标记,并在啮齿动物中进行评估。在雄性 ICR 小鼠的生物分布研究中,放射性配体 [ 18 F] 9或 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[ 18 F]fluoroethoxy)-1 H -吲哚被发现显示出高脑摄取和高脑血比。用选择性σ 2对动物进行预处理受体配体 CM398 以剂量依赖性方式导致放射性配体的脑摄取 (29%–54%) 和脑血比 (60%–88%) 显着降低,表明 [...] 18 F] 9到σ 2大脑中的受体。此外,雄性ICR小鼠的离体放射自显影显示脑中[ 18 F] 9的区域异质特异性结合,这与σ 2受体的分布模式一致。动态正电子发射断层扫描成像证实了 [ 18 F] 9的区域不同分布和高水平的特异性结合在大鼠脑中,以及适当的组织动力学。总之,我们目前的研究结果表明,新型放射性配体 [ 18 F] 9作为大脑中σ 2受体的第一个高度特异性和有前景的显像剂。