GluN2B亚基靶向型中枢神经系统正电子示踪剂的开发

GluN2B, one subunit of the glutamate receptor, has been proved that it is related to a variety of central nervous system diseases. PET imaging targeting to GluN2B subunits is of great significance for the diagnosis and treatment of related CNS diseases, as well as the development of GluN2B antagonists. In the previous works, the applicant has developed a series of 11C-labeled GluN2B-selected PET tracers. The studies indicated that these PET tracers have specific binding to the GluN2B subunits in vitro. However, these 11C-labeled tracers have several limitations to in vivo PET imaging due to short half-life, difficulty to permeate through the blood-brain barrier (BBB). Compared to C-11 labeled tracers, F-18 labeled PET tracers with a moderate half-life, strong electronegativity and high hydrophobic ability, have drawn a lot of attention. Based on the previous research, this project proposed to develop a novel series of 18F-labeled 1H-pyrrolo[3,2-b]pyridine-core tracers targeting to GluN2B through structure-activity relationship study, in vitro activity test, biodistribution, autoradiography, PET imaging of rodents and quantitative analysis. This class of PET tracers is featured with high specific binding to GluN2B in vivo, high ability to permeate through BBB and good stability in vivo. It also provides scientific support for the diagnosis and treatment of related CNS diseases and promotes the development of GluN2B antagonist drugs.

谷氨酸受体亚基GluN2B与多种中枢神经系统疾病的发生发展密切相关，该靶点的PET显像对相关疾病的诊疗和靶点抑制剂药物的开发具有重要意义。申请人前期发展了C-11标记的GluN2B靶向型PET探针，研究表明该探针在体外与GluN2B靶点可特异性结合，但该探针的半衰期短、过脑量低，难以应用于活体脑疾病成像研究。鉴于F-18的半衰期适中、电负性强、脂溶性高等优点，F-18标记的GluN2B探针是目前研究的热点。本项目将依托申请人的前期研究基础，基于前期构建的吡咯并吡啶母核结构，通过构效关系研究、体外活性测试、生物体内分布、放射自显影、啮齿动物模型PET显像和定量分析等，拟开发一种体内特异性结合能力强、脑摄取量高、体内稳定性优异的F-18标记GluN2B靶向型PET探针，为该靶点相关中枢神经系统疾病的诊疗提供可靠方法，也为GluN2B选择性抑制剂药物的研发提供新的策略。

N-甲基-D-天门冬氨酸受体（NMDARs）通过调节兴奋性神经传导，在哺乳动物中枢神经系统（CNS）的生理功能，包括学习、记忆和突触可塑性等中发挥了关键作用。由于GluN2B亚基涉及到多种中枢神经系统疾病和神经退行性疾病的病理，因此它是NMDA受体临床（前）研究中最深入的亚型之一。在本项目中，我们开发了两个碳-11标记的用于正电子断层扫描（PET）的探针的合成与临床前评价，探针是具有N, N-二甲基-2-（1H-吡咯并[3,2-b]吡啶-1-基）乙酰胺结构的GluN2B选择性负变构调节剂（NAM）。用[11C]CH3I进行甲基化标记，以高放射化学收率（以[11C]CO2为起始原料，衰变校正后分别为28%和32%）得到两个高放射化学纯度（>99%）、高比活度（>74 GBq/μmol）的PET探针[11C]31和[11C]37（分别叫做[11C]N2B-1810和[11C]N2B-1903）。通过体外放射性自显影研究，探针[11C]31表现出对GluN2B亚基中等的特异性结合能力。然而，[11C]31的PET成像在脑部的摄取有限（最高0.5 SUV），我们推测这可能是[11C]31体内特异性结合能力较低，且代谢速率过快造成的。所以对于带有这类化学母核的化合物，正在进一步针对ADME进行药物化学范畴的优化。

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