Subtype-selective NMDA ligands for Alzheimer's Disease

项目概述：涉及N-甲基-D-天冬氨酸受体（NMDAR）中GluN 2B亚基的功能障碍 在神经退行性疾病如阿尔茨海默病（AD）和相关痴呆的生理病理学中。 GluN 2B亚单位的药理学调节调节突触可塑性和兴奋，代表了一种有吸引力的 治疗方法PET能够量化体内的生物化学过程，并且合适的GluN 2B配体 将大大提高我们对GluN 2B为基础的离子型谷氨酸信号的理解， 病理生理状况，否则无法通过离体（破坏性）分析获得。GluN 2B的定量 通过PET的活体脑将提供新的放射性核素的分布、靶向接合和剂量占用的评估。 GluN 2B靶向神经疗法。迄今为止，还没有成功的例子被证明可以对GluN 2B进行成像， 人类使用，代表我们在体内研究该靶点的能力的显著不足。因此，我们建议 开发一种新的PET配体，可以克服以前尝试的主要缺点（低脑渗透性/有限 靶特异性/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GluN 2B靶向配体，[18F] N2 B-0518显示出优异的效力、靶向选择性和高选择性。 特异性结合，但由于脑渗透性低和体内代谢快而停止。在我们的下一代， 我们成功地鉴定了一个先导分子N2 B-94，它对GluN 2B表现出高效力和选择性， 所有其他NMDAR亚单位。合成N2 B-94的11 C-同位素体，并进行初步PET成像研究。 证实了我们已经克服了GluN 2B配体开发的主要障碍，实现了：1）高脑 摄取; 2）高靶特异性，以及良好改善的体内稳定性。虽然N2 B-94是一个有希望的线索， 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， 寻求翻译跨物种成像研究，以实现活脑中GluN 2B的最佳定量。 基于N2 B-94为药物化学优化提供了经验证的命中，作为具体目标，我们将 设计并制备一系列适合用11 C或18F标记的GluN 2B调节剂，并评估它们的能力， 定量啮齿类动物和非人灵长类动物在药物激发期间的GluN 2B活性和变化，以及 放射自显影和生物学验证在死后的脑组织从高等物种。这项工作的影响是 不仅开发了第一个有效的和选择性的GluN 2B 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PET成像验证在更高的物种，以推进这种配体 用于神经退行性疾病的新型神经治疗剂的潜在临床转化和监测靶反应 疾病，包括AD。 相关性：该提案有可能改善公共卫生，帮助患有糖尿病的患者。 神经退行性疾病，包括AD，通过发现使用GluN 2B选择性 NMDAR PET配体。

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.