Subtype-selective NMDA ligands for Alzheimer's Disease

阿尔茨海默病的亚型选择性 NMDA 配体

• 批准号: 10355691
• 负责人: Steven H Liang
• 金额: $ 78.22万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/10355691
• 关键词: ABCB1 gene; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' 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; Pharmacology; 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; base; brain tissue; clinical translation; design; drug discovery; glutamatergic signaling; imaging study; improved; in vitro Assay; in vivo; in vivo evaluation; lipophilicity; next generation; nonhuman primate; novel; pharmacokinetics and pharmacodynamics; radioligand; receptor; response; uptake; ylide

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Glun2b亚基的功能障碍已实施 在神经退行性疾病的生理病理学中，例如阿尔茨海默氏病（AD）和相关痴呆症。 Glun2b亚基的药理调节调节合成的可塑性和兴奋，代表着一个有吸引力的 治疗方法。 PET能够在体内量化生化过程和合适的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 生理病理条件否则可以通过体内（破坏性）分析无法访问。量化glun2b 宠物生命的大脑将评估分配，目标参与和新的剂量占用 针对Glun2b的神经疗法。迄今 人类使用，代表了我们在体内研究该靶标的能力的严重缺陷。因此，我们建议 开发一种新型的宠物配体，可以克服先前尝试的主要缺点（低脑渗透性 /有限 目标特异性 /高亲脂性），作为药物发现的第一个翻译成像工具。 我们的第一代Glun2b靶向配体[18F] N2B-0518表现出极好的效力，目标选择性和高 特异性结合，但由于体内脑穿透力和快速代谢而停产。在我们的下一代中， 我们成功识别了铅分子N2B-94，该分子对Glun2b的效力和选择性很高 所有其他NMDAR亚基。合成了N2B-94的11C异位学和初步的PET成像研究 确认我们通过实现了Glun2b配体开发的主要障碍：1）高脑 吸收2）高靶特异性以及在体内稳定性得到良好改善。虽然N2B-94是一个有前途的领导 分子，具有较高脑穿透力较高的宠物配体，提高效力和适当的脑动力学的选择性是 寻求翻译的跨物种成像研究，以实现活大脑中Glun2b的最佳定量。 根据N2B-94为医学化学优化的效果，作为特定目标，我们将 设计并准备一系列可用于标记11C或18F标签的GLUN2B调制器，并评估其能力 量化啮齿动物和非人类素数中药物挑战期间的glun2b活性和变化，以及 来自较高物种的死后脑组织的放射自显影和生物学验证。这项工作的影响是 不仅要开发第一个有效和选择性的glun2b宠物配体来研究神经退行性疾病 - 相关的生物过程，但最终也通过较高物种的PET成像验证来推进这种配体 为了潜在的临床翻译和监测新型神经疗法的靶向反应 疾病，包括广告。 相关性：该提案有可能改善公共卫生并帮助患者 神经退行性疾病（包括AD）通过使用Glun2B选择性发现神经疗法 NMDAR宠物配体。