PET imaging of ionotropic glutamate receptor signaling in Alzheimer's disease

阿尔茨海默病中离子型谷氨酸受体信号传导的 PET 成像

• 批准号: 10574694
• 负责人: Steven H Liang
• 金额: $ 23.48万
• 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: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574694
• 关键词: AD transgenic mice; APP-PS1; Affinity; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid beta-Protein; Animals; Applications Grants; Astrocytes; Binding; Biological Process; Brain; Brain region; CSF1R gene; Characteristics; Chronic; Clinical Research; Clinical Trials; Correlation Studies; Development; Disease; Disease Progression; Disease model; Economic Burden; Foundations; Functional disorder; Glutamate Receptor; Glutamates; Goals; Human; Image; Imaging Device; Incidence; Inflammatory; Kinetics; Knowledge; Life Expectancy; Ligands; Maps; Measurement; Mediating; Medical; Memantine; Microglia; Monitor; Mus; N-Methyl-D-Aspartate Receptors; Neurodegenerative Disorders; Neuroimmune; Observational Study; Outcome; Pathogenesis; Pathologic; Pharmaceutical Preparations; Positron-Emission Tomography; Process; Receptor Signaling; Role; Signal Pathway; Signal Transduction; Societies; Symptoms; Synapses; Testing; Time; Tracer; Transgenic Organisms; Treatment Efficacy; United States; Work; cohort; cytokine; design; disease phenotype; drug development; drug discovery; efficacious treatment; excitotoxicity; healthy volunteer; imaging study; inhibitor; longitudinal positron emission tomography; molecular imaging; mouse model; neuroinflammation; neuron loss; neurotoxicity; non-invasive imaging; novel; outcome prediction; pre-clinical; tool; treatment response

Project Summary. There are no efficacious therapies available to halt or reverse AD progression, which is attributed, at least in part, to the lack of translational molecular imaging tools suitable for both preclinical disease models and humans to facilitate drug discovery and development. Therefore, the development of such tools for non-invasive assessment of AD progression and therapeutic efficacy hold promises to fill the gap of this urgent and unmet medical need. Chronic neuroinflammation has demonstrated a key role in the pathogenesis of AD. As such, activated microglia release high levels of pro-inflammatory cytokines that prompt the release of excessive glutamate from adjacent astrocytes. The resulting glutamate spillover activates extrasynaptic N-methyl-D-aspartate (NMDA) receptors (NMDARs), thereby leading to the loss of synaptic integrity and neuronal cell death. As a primary contributor to this process, the GluN2B subunit is enriched in detrimental extrasynaptic NMDARs, which represents a promising target for monitoring glutamate-triggered neurotoxicity in AD. Our strategy involves the use of a specific positron emission tomography (PET) tracer, [11C]Me-NB1, that targets GluN2B-carrying NMDARs. To date, [11C]Me-NB1 is the only GluN2B PET tracer that has been successfully validated in small animals and healthy humans. Preliminary studies have shown that [11C]Me-NB1-PET is highly suited for non- invasive mapping of the GluN2B subunit, with excellent target affinity and selectivity across different species. However, non-invasive assessment of the distribution and expression of GluN2B has not yet been conducted in AD and the availability of [11C]Me-NB1 now provides new opportunity to fill this fundamental knowledge gap. Accordingly, our proposed study will lay the foundation for an appropriately designed clinical study with AD patients and age-matched healthy volunteers using [11C]Me-NB1-PET in the subsequent R01 application. As our specific objectives, utilizing non-invasive [11C]Me-NB1-PET, we propose to directly monitor GluN2B changes in AD models and evaluate treatment response for novel microglia-modulating therapy in transgenic APP/PS1 mouse models. Following this, our long-term goal is to assess the utility of [11C]Me-NB1-PET as a translational molecular imaging tool to provide new information (neuroimmune function and NMDAR-mediated neurotoxicity) of AD pathophysiology, and to enable target engagement and evaluate treatment response in clinical trials of novel AD drugs.

项目摘要。目前还没有有效的疗法可以阻止或逆转 AD 的进展， 至少部分归因于缺乏适用于临床前疾病的转化分子成像工具 模型和人类，以促进药物发现和开发。因此，开发此类工具 AD 进展和治疗效果的非侵入性评估有望填补这一紧迫的空白 以及未满足的医疗需求。 慢性神经炎症已被证明在 AD 的发病机制中发挥着关键作用。如此一来，激活 小胶质细胞释放高水平的促炎细胞因子，促使细胞释放过量的谷氨酸 相邻的星形胶质细胞。由此产生的谷氨酸溢出会激活突触外 N-甲基-D-天冬氨酸 (NMDA) 受体（NMDAR），从而导致突触完整性丧失和神经元细胞死亡。作为初级 GluN2B 亚基是这一过程的贡献者，富含有害的突触外 NMDAR， 代表了监测 AD 中谷氨酸引发的神经毒性的一个有前途的目标。我们的战略涉及 使用特定的正电子发射断层扫描 (PET) 示踪剂 [11C]Me-NB1，其目标是携带 GluN2B NMDAR。迄今为止，[11C]Me-NB1 是唯一已在小样本中成功验证的 GluN2B PET 示踪剂。 动物和健康的人类。初步研究表明，[11C]Me-NB1-PET 非常适合非 GluN2B 亚基的侵入性作图，在不同物种之间具有出色的靶亲和力和选择性。 然而，尚未对 GluN2B 的分布和表达进行非侵入性评估。 AD 和 [11C]Me-NB1 的可用性现在为填补这一基础知识空白提供了新的机会。 因此，我们提出的研究将为适当设计的 AD 临床研究奠定基础 在随后的 R01 应用中使用 [11C]Me-NB1-PET 的患者和年龄匹配的健康志愿者。作为我们的 针对特定目标，利用非侵入性 [11C]Me-NB1-PET，我们建议直接监测 GluN2B 的变化 AD 模型并评估转基因 APP/PS1 中新型小胶质细胞调节疗法的治疗反应 鼠标模型。在此之后，我们的长期目标是评估 [11C]Me-NB1-PET 作为转化药物的效用 提供新信息的分子成像工具（神经免疫功能和 NMDAR 介导的神经毒性） AD 病理生理学的研究，并在临床试验中实现目标参与并评估治疗反应 新型 AD 药物。