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

项目摘要。没有有效的治疗方法可用于停止或逆转AD进展， 这至少部分归因于缺乏适用于临床前疾病的翻译分子成像工具， 模型和人类，以促进药物发现和开发。因此，开发这种工具， AD进展和治疗效果的非侵入性评估有望填补这一迫切需求的差距。 未满足的医疗需求。 慢性神经炎症在AD的发病机制中起着关键作用。因此，激活 小胶质细胞释放高水平的促炎细胞因子，其促使从神经细胞释放过量的谷氨酸。 邻近的星形胶质细胞由此产生的谷氨酸溢出激活突触外N-甲基-D-天冬氨酸（NMDA） 受体（NMDAR），从而导致突触完整性的丧失和神经元细胞死亡。作为主要 在这一过程中，GluN 2B亚基富含有害的突触外NMDAR， 代表了监测AD中谷氨酸触发的神经毒性的有希望的靶点。我们的战略包括 靶向GluN 2B携带的特异性正电子发射断层扫描（PET）示踪剂[11 C] Me-NB 1的用途 NMDAR。到目前为止，[11 C] Me-NB 1是唯一一种已在小型实验室中成功验证的GluN 2B PET示踪剂。 动物和健康的人类。初步研究表明，[11 C] Me-NB 1-PET非常适合非放射性物质。 GluN 2B亚基的侵入性作图，在不同物种之间具有优异的靶向亲和力和选择性。 然而，GluN 2B的分布和表达的非侵入性评估尚未进行。 AD和[11 C] Me-NB 1的可用性现在为填补这一基本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R 01应用中使用[11 C] Me-NB 1-PET的患者和年龄匹配的健康志愿者。作为我们 具体目标，利用非侵入性[11 C] Me-NB 1-PET，我们建议直接监测GluN 2B的变化， 转基因APP/PS1中AD模型和评价新型小胶质细胞调节疗法的治疗反应 小鼠模型。在此之后，我们的长期目标是评估[11 C] Me-NB 1-PET作为翻译的实用性。 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，并使目标参与和评估治疗反应的临床试验， 新型AD药物。

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.