Subtype-Selective Metabotropic Glutamate Receptor PET Ligands

亚型选择性代谢型谷氨酸受体 PET 配体

基本信息

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
项目类别：
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&apos 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

项目摘要

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 的生理功能是负向调节内源性谷氨酸的释放和释放。因此，mGluR2 的药理学调节具有吸引力。用于治疗神经系统疾病和神经退行性疾病的治疗方法，包括帕金森病、阿尔茨海默病和相关痴呆症 (ADRD) 是正电子发射断层扫描 (PET)。能够量化体内生化过程，合适的 mGluR2 配体将大大改善我们的研究了解不同病理生理中枢神经系统疾病下 mGluR2 介导的信号通路，否则通过 PET 对活体大脑中的 mGluR2 进行定量是无法获得的。评估新型 mGluR2 靶向药物的分布、靶点参与和药效反应迄今为止，还没有成功的例子可以对人体中的 mGluR2 进行成像以用于药物治疗。发现和临床应用，代表了我们体内研究该靶标的能力的显着缺陷。提议开发一种新型 PET 配体来填补这一空白，作为第一个平移成像工具。我们是第一批在跨物种中开发基于 mGluR2 配体的负变构调节剂 (NAM) 的团队 PET 研究，包括 [11C]QCA 然而，由于脑渗透性低和边缘，该配体已停止。作为我们的下一代，我们鉴定了一个先导分子 MG2-2112，它表现出很高的结合特异性。我们的初步评估证实我们已经克服了两个主要问题。通过实现以下目标来克服 mGluR2 配体开发的障碍：1) 显着提高的结合亲和力，代表迄今为止最好的化合物；2) 高脑通透性和靶点特异性（mGluR2- 的特征性高摄取）尽管 MG2-2112 是一种有希望的先导药物，但我们并不清楚它是否有效。 PET 定量在药物发现和临床转化的跨物种研究中令人满意。以MG2-2112为基准，同时制备一系列mGluR2特异性PET配体。优化以提高结合特异性和适当的大脑动力学，以及概念验证人脑组织，旨在识别最佳 mGluR2 配体并支持靶点参与研究和功效这项工作的影响不仅在于开发出第一个成功的高度特异性的测量。 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，但最终还通过高等物种的 PET 成像验证，以推进这种配体的潜在临床应用转化和监测神经退行性疾病新型神经疗法的目标反应和安全范围疾病，包括 AD。