Translation of GluN2B-selective PET radiopharmaceuticals in Alzheimers patients

GluN2B 选择性 PET 放射性药物在阿尔茨海默病患者中的应用

• 批准号: 10716786
• 负责人: JAMES J LAH
• 金额: $ 78.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716786
• 关键词: 3xTg-AD mouse; AD transgenic mice; Affinity; Age; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid beta-Protein; Animals; Autopsy; Autoradiography; Binding; Biological; Biological Process; Blood; Blood specimen; Brain; Brain region; Characteristics; Clinical; Clinical Trials; Cognition; Cognitive deficits; Correlation Studies; Data; Dementia; Development; Disease Progression; Disease model; Evaluation; Functional disorder; Future; Glutamates; Goals; Homeostasis; Human; Image; Imaging Device; Imaging ligands; In Vitro; Individual; Kinetics; Knowledge; Learning; Longitudinal Studies; Maps; Measures; Mediating; Medical; Memory; Metabolism; Methods; Monitor; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neuroimmune; Outcome Measure; Patient Selection; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Pilot Projects; Plasma; Play; Positron-Emission Tomography; Radiopharmaceuticals; Receptor Activation; Reporting; Role; Signal Transduction; Signal Transduction Pathway; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic Intervention; Tissues; Tracer; Translating; Translations; Treatment Efficacy; United States; Work; brain tissue; cohort; design; drug development; drug discovery; efficacious treatment; excitotoxicity; glutamatergic signaling; healthy volunteer; imaging biomarker; imaging study; in vivo; in vivo imaging; indexing; kinetic model; molecular imaging; mouse model; neuroinflammation; neurotoxicity; novel; pre-clinical; radiotracer; receptor function; synaptic function; targeted imaging; tau expression; tau-1; tool

Project Summary. At present, there are no efficacious therapies for Alzheimer’s disease (AD) to halt or slow disease progression, which is attributed, at least in part, to the lack of translational cross-species molecular imaging tools suitable for use in both preclinical disease models and in humans to facilitate drug discovery and development. Therefore, the development of translatable imaging biomarkers for non-invasive assessment of disease progression and therapeutic efficacy hold promises to fill this urgent and unmet medical need. N-Methyl-D-aspartate receptor (NMDAR) plays a pivotal role in the synaptic transmission and synaptic plasticity thought to underlie learning and memory. NMDAR activation has been implicated in AD related to synaptic dysfunction, which leads to gradual loss of synaptic function and correlates clinically with the progressive decline in cognition/memory of AD patients. Therefore, in vivo imaging of GluN2B is of paramount translational relevance as it would allow the assessment of GluN2B distribution and expression of AD patients, enabling correlational study between NMDAR-mediated excitotoxicity and neuroimmune factors during AD progression and providing target engagement tool to support novel AD pharmacotherapy. Herein, we propose the use of a novel imaging strategy for monitoring detrimental extrasynaptic NMDAR function in AD. Our strategy entails the use of a novel positron emission tomography (PET) tracer, [11C]Me-NB1, that targets GluN2B-carrying NMDAR. To date, [11C]Me-NB1 is the only GluN2B PET tracer that has been successfully validated in naïve animals and recently tested in a small number of healthy subjects. Our 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 patients and clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between NMDAR dysfunction and AD. The availability of [11C]Me-NB1 now provides new opportunity to fill this fundamental knowledge gap. Therefore, we have developed three objectives and hypothesis in this work: (1) A kinetic modeling approach and absolute quantification, and/or simplified graphical methods of [11C]Me-NB1 can be established in healthy controls; (2) PET quantification method will be translated into AD patients and we expect increased GluN2B binding in vitro and in vivo by [11C]Me-NB1-PET is positively correlated with AD- related brain regions in AD patients (versus controls); (3) As proof-of-concept, in transgenic AD mouse models, we anticipate that [11C]Me-NB1-PET can directly monitor GluN2B changes and enable target occupancy studies during novel AD therapy. Overall impact: The role of glutamate-induced neurotoxicity in AD renders NMDAR subtype GluN2B a potential drug and imaging target. [11C]Me-NB1-PET can not only track GluN2B changes and measure target occupancy during novel AD therapeutic interventions, but also will support smaller, shorter trials for proof of mechanism and also to facilitate optimal patient selection for clinical trials.

项目摘要。目前，阿尔茨海默氏病（AD）尚无有效的疗法来停止或缓慢疾病 进展至少部分归因于缺乏翻译的跨物种分子成像工具 适用于临床前疾病模型和人类使用，以促进药物发现和发育。 因此，开发可翻译成像生物标志物，用于非侵入性评估疾病进展 和治疗效率的保证有望满足这种紧急且未满足的医疗需求。 N-甲基-D-天冬氨酸接收器 （NMDAR）在突触传播和合成可塑性中起关键作用，并认为是学习的基础 记忆。 NMDAR激活与与突触功能障碍有关的AD涉及 突触功能并与AD患者认知/记忆的逐渐下降相关。所以， glun2b的体内成像具有至关重要的转化相关性，因为它将允许评估Glun2b AD患者的分布和表达，在NMDAR介导的兴奋性毒性和 AD进展过程中的神经免疫因素并提供目标参与工具以支持新型AD 药物治疗。 在此，我们建议使用一种新型的成像策略来监测有害的外部挑战NMDAR功能 在广告中。我们的策略需要使用新型正电子发射断层扫描（PET）示踪剂[11C] Me-NB1 glun2b携带nmdar。迄今为止，[11C] ME-NB1是唯一已成功验证的Glun2b宠物示踪剂 在幼稚的动物中，最近在少数健康受试者中进行了测试。我们的初步研究表明 [11C] ME-NB1-PET非常适合Glun2b亚基的无创映射，具有出色的目标亲和力和 不同物种的选择性。但是，对glun2b的分布和表达的非侵入性评估 尚未在AD患者中进行过，明确的证据仍然缺乏证明基础 NMDAR功能障碍与AD之间的机制和关系。 [11C] ME-NB1现在提供的可用性 填补这一基本知识差距的新机会。因此，我们建立了三个目标和假设 在这项工作中：（1）动力学建模方法和绝对定量和/或简化的图形方法 [11C] ME-NB1可以在健康对照中建立； （2）PET定量方法将转化为AD患者 我们期望通过[11C] me-nb1-pet在体外和体内增加glun2b的结合增加与ad-呈正相关的 AD患者的相关大脑区域（相对于对照组）； （3）作为概念验证，在转基因AD鼠标模型中，我们 预计[11C] ME-NB1-PET可以直接监视Glun2b的变化，并使目标占用研究在 新型广告疗法。总体影响：谷氨酸诱导的神经毒性在AD中的作用使NMDAR亚型Glun2b 潜在的药物和成像靶标。 [11C] ME-NB1-PET不仅可以跟踪GLUN2B的变化和测量目标 新颖的广告热干预期间的占用率，但也将支持较小的，较短的试验以证明 机制，还可以促进最佳的患者选择进行临床试验。