Subtype-Selective Metabotropic Glutamate Receptor PET Ligands

项目摘要。mGluR 2的生理功能是负调节内源性谷氨酸释放， 保护神经元免受兴奋性毒性。因此，mGluR 2的药理学调节代表了一种有吸引力的方法 用于治疗神经障碍和神经变性疾病的治疗方法，包括 帕金森病、阿尔茨海默病和相关痴呆症（ADRD）。正电子发射断层扫描（PET）是 能够在体内定量生化过程，并且合适的mGluR 2配体将显著改善我们的研究。 了解不同病理生理学CNS疾病下mGluR 2介导的信号通路，否则 离体（破坏性）分析无法获得。通过PET定量活脑中的mGluR 2将提供 评估新型mGluR 2靶向的药物的分布、靶向结合和药效学反应 神经治疗学到目前为止，还没有成功的例子被证明可以对人体中的mGluR 2进行成像，用于药物治疗。 发现和临床应用，代表了我们在体内研究该靶点的能力的显著不足。所以我们 建议开发一种新的PET配体，可以填补这一空白，作为第一个平移成像工具。 我们是第一个在跨物种中开发基于负变构调节剂（NAM）的mGluR 2配体的团队 PET研究，包括[11 C]QCA。然而，这种配体由于脑渗透率低和边缘化而被停用。 体内结合特异性。作为我们的下一代，我们确定了一个先导分子，MG 2 -2112，它表现出很高的 结合亲和力和优异的选择性。我们的初步评估证实，我们已经克服了两个主要的 mGluR 2配体开发的障碍，通过实现：1）显著改善的结合亲和力，代表 迄今为止最好的化合物;和2）高脑渗透性和靶特异性（在mGluR 2中的特征性高摄取）。 富含纹状体和低mGluR 2-贫乏的丘脑/脑桥）。虽然MG 2 -2112是一个有希望的线索，但我们不清楚它是否是 在药物发现和临床转化的跨物种研究中的PET定量令人满意。因此，我们将 推进MG 2 -2112作为基准，同时制备一系列mGluR 2特异性PET配体。进一步 优化改进的结合特异性和适当的脑动力学，以及概念验证 人脑组织，以鉴定最佳mGluR 2配体并支持靶向接合研究和功效 药物发现中的测量。这项工作的影响不仅是开发出第一个成功的高度特定的 mGluR 2 PET配体用于研究神经系统疾病和神经退行性疾病相关的生物学 过程，但最终，通过PET成像验证在更高的物种，以推进这种配体的潜在临床 用于神经退行性疾病新型神经治疗剂的翻译和监测靶反应和安全范围 疾病，包括AD。

Project Summary. The physiological function of mGluR2 is to negatively regulate endogenous glutamate release and protect neurons against excitotoxicity. Therefore pharmacological modulation of mGluR2 represents an attractive therapeutic approach for the treatment of neurological disorders and neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and related dementias (ADRD). Positron emission tomography (PET) is capable of quantifying biochemical processes in vivo, and a suitable mGluR2 ligand would substantially improve our understanding of mGluR2-mediated signaling pathway under different pathophysiological CNS disorders, otherwise inaccessible by ex vivo (destructive) analysis. Quantification of mGluR2 in living brain by PET would provide the assessment of distribution, target engagement and pharmacodynamic response of novel mGluR2-targeted neurotherapeutics. To date, no successful examples have been demonstrated to image mGluR2 in humans for drug discovery and clinical use, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to develop a novel PET ligand that can fill this void, as the first translational imaging tool. We are the first groups to develop negative allosteric modulator (NAM) based mGluR2 ligands in cross-species PET studies, including [11C]QCA. However, this ligand was discontinued due to low brain penetration and marginal binding specificity in vivo. As our next generation, we identified a lead molecule, MG2-2112, which showed high binding affinity and excellent selectivity. Our preliminary evaluation confirmed that we have overcome the two major obstacles for mGluR2 ligand development by achieving: 1) substantially-improved binding affinity, representing the best compound to date; and 2) high brain permeability and target specificity (characteristic high uptake in mGluR2- rich striatum and low in mGluR2-poor thalamus/pons). Though MG2-2112 is a promising lead, we are not clear if it is satisfactory for PET quantification in cross-species study for drug discovery and clinical translation. Thus, we will advance MG2-2112 as a benchmark and concurrently prepare a series of mGluR2-specific PET ligands. Further optimization for improved binding specificity and proper brain kinetics, as well as proof-of-concept validations on human brain tissues, are sought to identify optimal mGluR2 ligands and support target engagement study and efficacy measurement in drug discovery. The impact of this work is not only to develop the first successful highly-specific mGluR2 PET ligand for the study of neurological disorders and neurodegenerative diseases-related biological processes, but also ultimately, via PET imaging validation in higher species, to advance this ligand for potential clinical translation and monitor target response and safety margins of novel neurotherapeutics for neurodegenerative diseases, including AD.