Development of a carbon-11 PET radiotracer for imaging TRPC5 in the brain.
Development of a carbon-11 PET radiotracer for imaging TRPC5 in the brain.
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DOI：
10.1039/c9ob00893d
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发表时间：
2019-06
影响因子：
3.2
通讯作者：
Yanbo Yu;Qianwa Liang;Hui Liu;Zonghua Luo;Hongzhen Hu;J. Perlmutter;Z. Tu
中科院分区：
文献类型：
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作者：
Yanbo Yu;Qianwa Liang;Hui Liu;Zonghua Luo;Hongzhen Hu;J. Perlmutter;Z. Tu
瞬时受体电位通道亚家族成员5 （TRPC5）是脑内广泛表达的钙渗透阳离子通道。越来越多的证据表明，它在包括抑郁和焦虑在内的精神疾病中起着至关重要的作用。正电子发射断层扫描（PET）结合TRPC5特异性放射配体可能为研究TRPC5在动物疾病模型中的功能提供独特的工具，从而指导靶向TRPC5的药物开发。为了开发TRPC5 PET放射性示踪剂，我们选择了有效的TRPC5抑制剂HC608，通过n -去甲基酰胺前体7与[11C]碘化甲基反应进行C-11放射性合成。在优化的条件下，[11C]HC608具有良好的放射化学产率（25±5%），高化学和放射化学纯度（bbb99 %）和高比活性（204-377 GBq μmol-1，衰变校正到轰击结束，EOB）。体外放射自显影研究显示[11C]HC608特异性结合TRPC5。此外，在啮齿类动物体内对[11C]HC608的初步体内评价和非人灵长类动物脑内的微pet研究进一步表明[11C]HC608能够穿透血脑屏障并在脑内充分积累。这些结果表明[11C]HC608有潜力成为活体TRPC5成像的PET示踪剂。
The transient receptor potential channel subfamily member 5 (TRPC5) is a calcium permeable cation channel widely expressed in the brain. Accumulating evidence indicates that it plays a crucial role in psychiatric disorders including depression and anxiety. Positron emission tomography (PET) combined with a TRPC5 specific radioligand may provide a unique tool to investigate the functions of TRPC5 in animal disease models to guide drug development targeting TRPC5. To develop a TRPC5 PET radiotracer, the potent TRPC5 inhibitor HC608 was chosen for C-11 radiosynthesis through the N-demethyl amide precursor 7 reacting with [11C]methyl iodide. Under optimized conditions, [11C]HC608 was achieved with good radiochemical yield (25 ± 5%), high chemical and radiochemical purity (>99%), and high specific activity (204-377 GBq μmol-1, decay corrected to the end of bombardment, EOB). The in vitro autoradiography study revealed that [11C]HC608 specifically binds to TRPC5. Moreover, initial in vivo evaluation of [11C]HC608 performed in rodents and the microPET study in the brain of non-human primates further demonstrated that [11C]HC608 was able to penetrate the blood brain barrier and sufficiently accumulate in the brain. These results suggest that [11C]HC608 has the potential to be a PET tracer for imaging TRPC5 in vivo.