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，阿尔茨海默病（Alzheimer's disease，AD）还没有有效的治疗方法来阻止或延缓疾病的发展 进展，这至少部分归因于缺乏翻译跨物种分子成像工具 适用于临床前疾病模型和人类以促进药物发现和开发。 因此，开发可翻译的成像生物标志物用于疾病进展的非侵入性评估 和治疗效果有望满足这一迫切和未满足的医疗需求。N-甲基-D-天冬氨酸受体 （NMDAR）在突触传递和突触可塑性中起着关键作用，被认为是学习和 记忆NMDAR激活与突触功能障碍相关的AD有关，这导致NMDAR的逐渐丧失。 突触功能，并在临床上与AD患者认知/记忆的进行性下降相关。因此，我们认为， GluN 2B的体内成像具有重要的翻译相关性，因为它可以评估GluN 2B AD患者的分布和表达，使NMDA受体介导的兴奋性毒性和 AD进展过程中的神经免疫因子，并提供靶点参与工具以支持新型AD 药物治疗. 在此，我们提出使用一种新的成像策略来监测有害的突触外NMDAR功能， 在AD中。我们的策略需要使用一种新的正电子发射断层扫描（PET）示踪剂，[11 C] Me-NB 1，靶向 携带GluN 2B的NMDAR。到目前为止，[11 C] Me-NB 1是唯一一种已成功验证的GluN 2B PET示踪剂 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， [11 C] Me-NB 1-PET非常适合GluN 2B亚基的非侵入性定位，具有优异的靶向亲和力， 对不同物种的选择性。然而，GluN 2B的分布和表达的非侵入性评估 尚未在AD患者中进行，仍缺乏明确的证据证明潜在的 机制以及NMDAR功能障碍与AD之间的关系。[11 C] Me-NB 1的可用性现在提供了 填补这一基本知识空白的新机会。因此，我们提出了三个目标和假设 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， [11 C] Me-NB 1可在健康对照中建立;（2）PET定量方法将被翻译到AD患者中 并且我们预期[11 C] Me-NB 1-PET在体外和体内增加的GluN 2B结合与AD正相关。 AD患者（与对照组相比）的相关脑区;（3）作为概念验证，在转基因AD小鼠模型中，我们 预计[11 C] Me-NB 1-PET可以直接监测GluN 2B的变化，并在研究过程中进行目标占用研究。 新的AD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GluN 2B 潜在的药物和成像靶点。[11 C] Me-NB 1-PET不仅可以跟踪GluN 2B的变化， 新的AD治疗干预期间的占用率，但也将支持更小，更短的试验，以证明 机制，并促进临床试验的最佳患者选择。