Subtype-Selective Metabotropic Glutamate Receptor PET Ligands

亚型选择性代谢型谷氨酸受体 PET 配体

• 批准号: 10576674
• 负责人: Steven H Liang
• 金额: $ 81.64万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576674
• 关键词: ABCB1 gene; Affinity; Alzheimer' s disease related dementia; Autopsy; Autoradiography; Benchmarking; Binding; Binding Proteins; Biochemical Process; Biodistribution; Biological; Biological Assay; Biological Process; Blood specimen; Brain; Cells; Central Nervous System Diseases; Characteristics; Chemistry; Clinical; Corpus striatum structure; Development; Docking; Dose; Drug Targeting; Evaluation; Glutamates; Goals; Human; Image; Imaging Device; In Vitro; Kinetics; Knockout Mice; Knowledge; Label; Lead; Libraries; Ligands; Liver Microsomes; Measurement; Mediating; Metabotropic Glutamate Receptors; Molecular; Monitor; National Institute of Mental Health; Neurodegenerative Disorders; Neurons; Parkinson Disease; Penetration; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Physiological; Plasma; Plasma Proteins; Pontine structure; Positron-Emission Tomography; Radiolabeled; Research; Rodent; Safety; Selection Criteria; Series; Signal Pathway; Site; Specificity; Testing; Thalamic structure; Therapeutic; Toxic effect; Translations; United States; Validation; Work; biomarker signature; brain tissue; candidate marker; clinical development; clinical translation; design; drug discovery; excitotoxicity; image translation; imaging biomarker; imaging study; improved; in vivo; in vivo evaluation; kinetic model; lipophilicity; metabotropic glutamate receptor 2; molecular imaging; mouse model; nervous system disorder; next generation; nonhuman primate; novel; pharmacokinetics and pharmacodynamics; pharmacologic; radioligand; receptor; response; uptake; validation studies

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.

项目摘要。 mglur2的身体功能是负调节内源性谷氨酸释放和 保护神经元免受兴奋性毒性。因此，MGLUR2的药物调制代表了一个吸引人的 治疗神经系统疾病和神经退行性疾病的治疗方法，包括 帕金森氏病，阿尔茨海默氏病和相关痴呆症（ADRD）。正电子发射断层扫描（PET）是 能够在体内量化生化过程以及合适的MGLUR2配体将大大改善我们的 了解MGLUR2介导的信号通路在不同的病理生理CNS疾病下，否则 通过离体（破坏性）分析无法访问。 PET对生物大脑中MGLUR2的量化将提供 评估新型MGLUR2靶向的分布，目标参与和药效学反应 神经治疗学。迄今为止，尚未证明成功的示例以在人类中的MGLUR2形象形象 发现和临床用途，代表了我们在体内研究该靶标的能力的严重缺陷。因此，我们 提议开发一种新型的宠物配体，可以填补这一空白，作为第一个翻译成像工具。 我们是第一批基于跨物种的基于负变构调制器（NAM）的MGLUR2配体的组 宠物研究，包括[11C] QCA。但是，由于脑穿透和边缘低，该配体被停用 体内结合特异性。作为下一代，我们确定了铅分子MG2-2112，该分子显示高 结合亲和力和出色的选择性。我们的初步评估证实了我们已经克服了这两个主要 通过实现MGLUR2配体开发的障碍：1）实质性增强的结合亲和力，代表 迄今为止的最佳化合物； 2）高脑渗透性和靶标特异性（MGLUR2-的特征高吸收 富含纹状体，低纹状体和低纹状体丘脑/pons）。尽管MG2-2112是一个有前途的领导，但我们尚不清楚是否是 在药物发现和临床翻译的跨物种研究中，PET定量令人满意。那我们会的 提前MG2-2112作为基准，并同时准备一系列MGLUR2特异性宠物配体。更远 优化以提高结合特异性和适当的脑动力学，以及对概念验证的验证 人们感觉到人脑组织以识别最佳MGLUR2配体并支持目标参与研究和效率 药物发现的测量。这项工作的影响不仅是开发第一个成功的高度特异性 MGLUR2 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，但最终也通过较高物种的PET成像验证，以推进该配体的潜在临床 神经退行性新型神经疗法的翻译和监测目标响应和安全边缘 疾病，包括广告。