PET ligand development for mGlu2 based on negative allosteric modulators

项目概述：本项目的目标是开发第一个基于负变构调节剂（NAM）的正电子 代谢型谷氨酸受体亚型2（mGlu 2）的发射断层扫描（PET）配体，基于阴性 变构调节作为药物发现的成像生物标志物。 mGlu 2的生理功能是负调节内源性谷氨酸的释放，保护神经元 对抗兴奋性毒性调节mGlu 2的持续努力代表了治疗糖尿病的广泛药理学方法。 治疗中枢神经系统疾病，包括药物成瘾、抑郁症、精神分裂症、帕金森病和阿尔茨海默病 疾病作为一种非侵入性成像技术，PET能够量化体内的生化过程， 合适mGlu 2 PET配体将显著提高我们对基于mGlu 2的谷氨酸能信号传导的理解 在正常和疾病条件下，否则无法进行离体（破坏性）分析。此外，委员会认为， 通过PET定量mGlu 2将提供分布、靶点结合和剂量占用的评估 mGlu 2靶向神经治疗新方法到目前为止还没有成功的例子已经证明了图像 mGlu 2，代表我们在体内研究该靶点的能力的显著不足。因此，我们建议开发 mGlu 2的PET配体，其将克服先前PET配体的两个主要缺点（低脑摄取和 有限的靶点特异性），并成为第一个用于药物发现和临床转化的mGlu 2显像剂。 第一个基于NAM的mGlu 2配体[11 C]QCA最近由MGH的PI开发。[11 C]QCA显示 对mGlu 2具有优异的体外特异性结合和靶向选择性，但由于脑损伤低而停止 渗透。在我们的第二代mGlu 2 NAM中，我们鉴定了具有高效力的铅吡啶化合物， 对mGlu 2的选择性。该导联的11 C同位素显示合理的脑摄取（1.1 SUV）和靶向 参与治疗前研究（约60%阻断）。虽然我们的主要候选人是一个有希望的领导， 开发新的mGlu 2靶向靶向接合工具，具有更高脑穿透性的PET配体， 为了提高mGlu 2的效能和选择性，需要增加特异性结合比率以实现mGlu 2的最佳成像和定量。 在本提案中，我们将设计和制备一系列精心挑选的mGlu 2 NAM，放射性标记的顶级候选物， 与11 C或18F，并评估其定量mGlu 2活性的能力和在啮齿类动物中药物激发期间的变化， 非人灵长类动物。这项工作的影响不仅是开发第一个有效的和选择性的mGlu 2 PET NAM 配体的药物发现，但也最终，准备这种成像工具的潜在临床翻译和监测 mGlu 2治疗剂在人脑中的直接作用。有效mGlu 2-的靶标验证和占有率 在这项工作中，还可以通过mGlu 2 PET配体来确定和量化相关治疗。 相关性：该提案有可能改善公共卫生并帮助患有CSN疾病的患者 通过发现使用mGlu 2 PET配体的神经疗法。

Project Summary: The goal of this project is to develop the first negative allosteric modulator (NAM)-based positron emission tomography (PET) ligand for metabotropic glutamate receptor subtype 2 (mGlu2) based on negative allosteric modulation as imaging biomarker for drug discovery. The physiological function of mGlu2 is to negatively regulate endogenous glutamate release and protect neurons against excitotoxicity. Continuous efforts to modulate mGlu2 represent a broad pharmacological approach for the treatment of CNS disorders, including drug addiction, depression, schizophrenia, Parkinson’s disease and Alzheimer’s disease. As a non-invasive imaging technology, PET is capable of quantifying biochemical processes in vivo, and a suitable mGlu2 PET ligand would substantially improve our understanding of mGlu2-based glutamatergic signaling under normal and disease conditions otherwise inaccessible by ex vivo (destructive) analysis. Furthermore, quantification of mGlu2 by PET would provide the assessment of distribution, target engagement and dose occupancy of mGlu2-targeted new neurotherapeutics. To date there is no successful examples have been demonstrated to image mGlu2, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to develop a PET ligand for mGlu2 that will overcome the two major shortcomings of previous PET ligands (low brain uptake and limited target specificity) and be the first mGlu2 imaging agent for drug discovery and clinical translation. The first NAM-based mGlu2 ligand, [11C]QCA, was recently developed by the PI at MGH. [11C]QCA showed excellent in vitro specific binding and target selectivity towards mGlu2, but was discontinued due to low brain penetration. In our second generation mGlu2 NAMs, we identify a lead pyridine compound with high potency and selectivity towards mGlu2. A 11C-isotopolgue of this lead showed reasonable brain uptake (1.1 SUV) and target engagement in pretreatment studies (~60% blockade). Though our lead candidate is a promising lead for the development of new mGlu2-targeted target engagement tool, PET ligands with higher brain penetration, improved potency and selectivity, increased specific binding ratios are needed for optimal imaging and quantification of mGlu2. In this proposal, we will design and prepare a series of carefully chosen mGlu2 NAMs, radiolabel top candidates with 11C or 18F, and evaluate their ability to quantify mGlu2 activity and changes during drug challenges in rodents and nonhuman primates. The impact of this work is not only to develop the first potent and selective mGlu2 PET NAM ligand for drug discovery, but also ultimately, to prepare this imaging tool for potential clinical translation and monitor direct effect of mGlu2 therapeutic agents in human brain. The target validation and occupancy for efficacious mGlu2- related treatment can also be determined and quantified by the mGlu2 PET ligands in this work. Relevance: This proposal has the potential to improve public health and help patients suffering from CSN disorders through the discovery of neurotherapeutics using mGlu2 PET ligands.