AMPAR ligand discovery for Alzheimer's disease

AMPAR 配体发现治疗阿尔茨海默病

基本信息

批准号：
10280112
负责人：
Steven H Liang
金额：
$ 38.42万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-03-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10280112
关键词：
ABCB1 gene AMPA Receptors Affinity Alzheimer&apos s Disease Alzheimer&apos s disease patient Autopsy Autoradiography Binding Biochemical Process Biodistribution Biological Biological Assay Biological Process Blood specimen Brain Characteristics Chemistry Clinical Development Docking Dose Evaluation Excitatory Synapse Functional disorder Generations Glutamates Goals Human Image Imaging Device In Vitro Kinetics Knockout Mice Label Lead Learning Libraries Ligands Long-Term Potentiation Mediating Memory Messenger RNA Metabolic Clearance Rate Modeling Molecular Monitor National Institute of Mental Health Nervous System control Neuraxis Neurodegenerative Disorders Parents Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Positioning Attribute Positron Radioactivity Radiolabeled Rodent Scientific Advances and Accomplishments Site Specificity System Testing Therapeutic Transducers Transgenic Organisms Translations United States Validation Western Blotting Work base brain tissue clinical translation design drug discovery glutamatergic signaling imaging study improved in vitro Assay in vivo in vivo evaluation mouse model neurotransmission nonhuman primate novel radioligand receptor response stable cell line uptake

项目摘要

Project Summary. AMPA receptors (AMPARs) are the principle transducers of fast glutamatergic neurotransmission throughout the central nervous system (CNS), where they control the strength of excitatory synapses and modulate long-term potentiation (LTP) - a fundamental mechanism of learning and memory function. AMPAR dysfunction has been implicated in a variety of neurodegenerative diseases, including Alzheimer’s disease (AD). Therefore pharmacological modulation of AMPAR represents an attractive therapeutic approach. Positron emission tomograohy (PET) is capable of quantifying biochemical processes in vivo, and a suitable AMPAR ligand would substantially improve our understanding of AMPAR-mediated ionotropic glutamate signaling under different pathophysiological AD conditions, otherwise inaccessible by ex vivo (destructive) analysis. Quantification of AMPAR in living brain by PET would provide the assessment of distribution, target engagement and dose occupancy of new AMPAR-targeted neurotherapeutics. To date, no successful examples have been demonstrated to image GluA2-specific AMPAR 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 AMPAR GluA2-specific ligands, including [11C]AMPA-1905 (developed by the PI in 2020). However, this ligand was discontinued due to marginal binding specificity in vivo. In our 2nd generation, we identified a lead molecule, AMPA-2076, which showed high binding affinity and excellent selectivity over all other iGlu receptors. An 18F-isotopologue of AMPA-2076 was synthesized and preliminary PET imaging studies confirmed that we have overcome two major obstacles for GluA2-specific AMPAR ligand development by achieving: 1) substantially-improved in vivo stability in the brain and 2) high target specificity. Though AMPA-2076 is a promising lead molecule for the development of new GluA2-targeted AMPAR ligands, further optimization for improved binding specificity with proper brain kinetics are sought for translational cross-species imaging studies to achieve optimal AMPAR (GluA2 subunit) quantification in the living brain for drug discovery and clinical translation for AD patients. On the basis that AMPA-2076 serves a validated lead for medicinal chemistry optimization, as specific goals, we will design and prepare a focused library of GluA2-specific AMPAR modulators amenable for labeling with 11C or 18F, and evaluate their ability to quantify AMPAR activity and changes during drug challenge in rodents and nonhuman primates, as well as autoradiography and biological validation in postmortem human brain tissues. The impact of this work is not only to develop the first successful high-affinity and selective AMPAR 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.

AMPA 受体 (AMPAR) 是快速谷氨酸能神经传递的主要传感器。整个中枢神经系统 (CNS)，它们控制兴奋性突触的强度并调节长时程增强 (LTP) - AMPAR 功能障碍的基本机制。与多种神经退行性疾病有关，包括阿尔茨海默病（AD）。 AMPAR 的药理学调节代表了一种有吸引力的治疗方法。（PET）能够量化体内的生化过程，并且合适的 AMPAR 配体将基本上提高我们对不同病理生理 AD 下 AMPAR 介导的离子型谷氨酸信号传导的理解条件下，否则无法通过 PET 对活体大脑中的 AMPAR 进行定量（破坏性）。将提供新 AMPAR 目标的分布、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 GluA2 特异性 AMPAR 进行成像。药物发现和临床使用，代表了我们体内研究该靶标的能力的显着缺陷。我们建议开发一种新型 PET 配体来填补这一空白，作为第一个平移成像工具。我们是第一批开发 AMPAR GluA2 特异性配体的团队，包括 [11C]AMPA-1905（由 PI 于 2020 年）但是，由于体内结合特异性有限，该配体已停止使用。我们鉴定了一种先导分子 AMPA-2076，与其他分子相比，它表现出高结合亲和力和出色的选择性合成了 AMPA-2076 的 18F-同位素体，并得到了初步 PET 成像研究的证实。我们通过实现以下目标克服了 GluA2 特异性 AMPAR 配体开发的两个主要障碍：1) 尽管 AMPA-2076 是一种很有前途的药物，但其在大脑中的体内稳定性得到了显着改善，并且 2) 靶标特异性很高。用于开发新的 GluA2 靶向 AMPAR 配体的先导分子，进一步优化以改善结合寻求具有适当脑动力学的特异性以进行跨物种转化成像研究，以实现最佳效果活体大脑中的 AMPAR（GluA2 亚基）定量，用于 AD 患者的药物发现和临床转化。基于 AMPA-2076 为药物化学优化提供了经过验证的先导化合物，作为具体目标，我们将设计和准备一个专门的 GluA2 特异性 AMPAR 调节剂库，适合用 11C 或 18F 标记，并评估他们量化啮齿动物和非人类药物挑战期间 AMPAR 活性和变化的能力灵长类动物，以及死后人类脑组织的放射自显影和生物验证。工作不仅是开发第一个成功的高亲和力和选择性 AMPAR PET 配体，用于研究神经退行性疾病相关的生物过程，但最终也通过更高级别的 PET 成像验证种，以推进该配体的潜在临床转化并监测新型神经治疗药物的靶标反应用于神经退行性疾病，包括 AD。