Discovery and development of brain-penetrant (18)F-labeled radioligands for neuroimaging of the sigma-2 receptors.
Discovery and development of brain-penetrant (18)F-labeled radioligands for neuroimaging of the sigma-2 receptors.
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发现和开发用于 sigma-2 受体神经成像的脑渗透性 18F 标记放射性配体
DOI：
10.1016/j.apsb.2021.08.029
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发表时间：
2022-03
影响因子：
14.5
通讯作者：
Jia, Hongmei
中科院分区：
文献类型：
--
作者：
Zhang, Ying;Wang, Tao;Zhang, Xiaojun;Deuther-Conrad, Winnie;Fu, Hualong;Cui, Mengchao;Zhang, Jinming;Brust, Peter;Huang, Yiyun;Jia, Hongmei
我们发现并合成了一系列吲哚衍生物作为新型σ 2受体配体。两个具有高σ2受体亲和力和亚型选择性的配体，然后用F-18以良好的放射化学产率和纯度进行放射性标记，并在啮齿动物中进行评价。在雄性ICR小鼠的生物分布研究中，发现放射性配体[18 F]9或1-（4-（5，6-二甲氧基异吲哚啉-2-基）丁基）-4-（2-[18 F]氟乙氧基）-1H-吲哚显示高脑摄取和高脑血比。用选择性σ2受体配体CM 398预处理动物导致放射性配体的脑摄取（29%-54%）和脑-血比（60%-88%）以剂量依赖性方式显著降低，表明[18 F]9与脑中σ2受体的高且可饱和的特异性结合。此外，雄性ICR小鼠的离体放射自显影显示脑中[18 F]9的区域异质性特异性结合，这与σ2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大鼠脑中[18 F]9的区域性不同分布和高水平特异性结合，沿着适当的组织动力学。总之，我们当前研究的结果表明，新型放射性配体[18 F]9是脑中σ2受体的第一种高度特异性和有前途的成像剂。放射性配体[18F]9具有有利的特性，包括纳摩尔亲和力、高选择性、适当的动力学和最高水平的脑摄取、脑血比和特异性结合，用于σ2受体的神经成像。
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. Radioligand [18F]9 possesses favorable characteristics including nanomolar affinity, high selectivity, appropriate kinetics, and the highest levels of brain uptake, brain-to-blood ratio, and specific binding for neuroimaging of the σ2 receptors.
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影响因子：
5.2
作者：
Matsushita Y;Nakagawa H;Koike K
通讯作者：
Koike K
σ2受体：一种用于癌症成像和治疗的新型蛋白质。
影响因子：
7.3
作者：
Mach, Robert H.;Zeng, Chenbo;Hawkins, William G.
通讯作者：
Hawkins, William G.
影响因子：
8.8
作者：
Al-Nabulsi, I;Mach, RH;Wheeler, KT
通讯作者：
Wheeler, KT
影响因子：
7.3
作者：
Bautista-Aguilera, Oscar M.;Budni, Josiane;Marco-Contelles, Jose
通讯作者：
Marco-Contelles, Jose
DOI：
10.1007/s11426-006-0169-z
发表时间：
2006-04-01
期刊：
SCIENCE IN CHINA SERIES B-CHEMISTRY
影响因子：
--
作者：
Fan Caiyun;Jia Hongmei;Liu Boli
通讯作者：
Liu Boli