Subtype-selective NMDA ligands for Alzheimer's Disease

阿尔茨海默病的亚型选择性 NMDA 配体

基本信息

批准号：
10593906
负责人：
Steven H Liang
金额：
$ 78.1万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593906
关键词：
ABCB1 gene Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Autopsy Autoradiography Binding Binding Proteins Biochemical Process Biodistribution Biological Biological Assay Biological Process Blood specimen Brain Clinical Development Docking Dose Evaluation Functional disorder Generations Glutamates Goals Human Image Imaging Device In Vitro Kinetics Knowledge Label Lead Ligands Liver Microsomes Metabolism Midbrain structure Modeling Molecular Monitor N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurodegenerative Disorders Parents Patients Penetration Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Plasma Plasma Proteins Pontine structure Positron-Emission Tomography Public Health Radioactivity Radiolabeled Reaction Rodent Scientific Advances and Accomplishments Series Site Specificity Standardization Synaptic plasticity System Testing Therapeutic Toxic effect Translations United States Validation Work antagonist aspartate receptor brain tissue clinical translation design drug discovery glutamatergic signaling image translation imaging study improved in vitro Assay in vivo in vivo evaluation lipophilicity next generation nonhuman primate novel pharmacokinetics and pharmacodynamics pharmacologic radioligand receptor response uptake ylide

项目摘要

Project Summary: Dysfunction of GluN2B subunit in the N-Methyl-D-aspartic acid receptor (NMDAR) is implicated in the physiopathology of neurodegenerative diseases such as Alzheimer’s disease (AD) and related dementia. Pharmacological modulation of GluN2B subunit regulates synaptic plasticity and excitation, representing an attractive therapeutic approach. PET is capable of quantifying biochemical processes in vivo, and a suitable GluN2B ligand would substantially improve our understanding of GluN2B-based ionotropic glutamate signaling under physiopathological conditions otherwise inaccessible by ex vivo (destructive) analysis. Quantification of GluN2B in living brain by PET would provide the assessment of distribution, target engagement and dose occupancy of new GluN2B-targeted neurotherapeutics. To date, no successful examples have been demonstrated to image GluN2B for human 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 overcome major drawbacks of previous attempts (low brain permeability / limited target specificity / high lipophilicity), as the first translational imaging tool for drug discovery. Our first generation GluN2B-targeted ligand, [18F]N2B-0518 showed excellent potency, target selectivity and high specific binding, but was discontinued due to low brain penetration and fast metabolism in vivo. In our next generation, we successfully identified a lead molecule, N2B-94, which showed high potency and selectivity towards GluN2B over all other NMDAR subunits. An 11C-isotopologue of N2B-94 was synthesized and preliminary PET imaging studies confirmed that we have overcome the major obstacles for GluN2B ligand development by achieving: 1) high brain uptake; 2) high target specificity, as well as well-improved in vivo stability. Though N2B-94 is a promising lead molecule, PET ligands with higher brain penetration, improved potency and selectivity with proper brain kinetics are sought for translational cross-species imaging studies to achieve optimal quantification of GluN2B in the living brain. On the basis that N2B-94 serves a validated hit for medicinal chemistry optimization, as specific goals, we will design and prepare a series of GluN2B modulators amenable for labeling with 11C or 18F, and evaluate their ability to quantify GluN2B activity and changes during drug challenge in rodents and nonhuman primates, as well as autoradiography and biological validation in postmortem brain tissues from higher species. The impact of this work is not only to develop the first potent and selective GluN2B PET ligand for the study of neurodegenerative disease- 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 of novel neurotherapeutics for neurodegenerative diseases, including AD. Relevance: This proposal has the potential to improve public health and help patients suffering from neurodegenerative diseases, including AD, through the discovery of neurotherapeutics using GluN2B-selective NMDAR PET ligands.

项目摘要：N-甲基-D-天冬氨酸受体 (NMDAR) 中的 GluN2B 亚基功能障碍与此有关神经退行性疾病（例如阿尔茨海默病（AD）和相关痴呆症）的病理生理学。 GluN2B 亚基的药理学调节可调节突触可塑性和兴奋性，代表着一种有吸引力的 PET 能够量化体内生化过程，并提供合适的 GluN2B 配体。将大大提高我们对基于 GluN2B 的离子型谷氨酸信号传导的理解否则无法通过体外（破坏性）分析对 GluN2B 进行定量。 PET 活体大脑将提供新的分布、目标参与和剂量占用的评估迄今为止，还没有成功的例子可以对 GluN2B 进行成像。人类使用，代表我们体内研究该靶标的能力存在显着缺陷，因此，我们建议开发一种新型 PET 配体，可以克服先前尝试的主要缺点（低脑通透性/有限目标特异性/高亲脂性），作为药物发现的第一个转化成像工具。我们的第一代 GluN2B 靶向配体 [18F]N2B-0518 显示出优异的效力、靶点选择性和高特异性结合，但由于大脑渗透性低和体内新陈代谢快而被终止。我们成功鉴定了一个先导分子 N2B-94，它对 GluN2B 表现出高效能和选择性合成了 N2B-94 的所有其他 NMDAR 亚基并进行了初步 PET 成像研究。证实我们通过实现以下目标克服了 GluN2B 配体开发的主要障碍：1）高脑 2）高靶点特异性，以及良好的体内稳定性。分子、PET配体具有更高的脑渗透性、改善的效力和选择性以及适当的脑动力学寻求跨物种转化成像研究，以实现活体大脑中 GluN2B 的最佳定量。基于 N2B-94 为药物化学优化提供了有效的命中，作为具体目标，我们将设计和制备一系列适合用 11C 或 18F 标记的 GluN2B 调节剂，并评估它们的能力量化啮齿动物和非人灵长类动物药物挑战期间的 GluN2B 活性和变化，以及高等物种死后脑组织的放射自显影和生物验证这项工作的影响是。不仅是为了开发第一个有效且选择性的 GluN2B PET 配体用于神经退行性疾病的研究 - 相关的生物过程，但最终，通过高等物种的 PET 成像验证，以推进这种配体用于神经退行性疾病的新型神经治疗药物的潜在临床转化和监测目标反应疾病，包括 AD。相关性：该提案有可能改善公共卫生并帮助患有以下疾病的患者神经退行性疾病，包括 AD，通过使用 GluN2B 选择性神经疗法的发现 NMDAR PET 配体。