Translation of GluN2B-selective PET radiopharmaceuticals in Alzheimers patients

项目摘要。目前，对于阿尔茨海默病(AD)还没有有效的治疗方法来阻止或减缓疾病 进展，这至少部分归因于缺乏可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，以促进药物发现和开发。 因此，可翻译的成像生物标记物的发展无创性地评估疾病的进展 治疗效果有望满足这一紧迫而未得到满足的医疗需求。N-甲基-D-天冬氨酸受体 (NMDAR)在突触传递和突触可塑性中发挥着关键作用，这些突触可塑性是学习和 记忆。NMDAR激活与AD有关，与突触功能障碍有关，导致逐渐失去 突触功能与AD患者认知/记忆进行性下降相关。因此， GluN2B的体内成像具有最重要的翻译相关性，因为它将允许评估GluN2B AD患者的分布和表达，使NMDAR介导的兴奋性毒性与AD的相关性研究成为可能 阿尔茨海默病进展过程中的神经免疫因素和提供靶向参与工具以支持新型AD 药物疗法。 在此，我们建议使用一种新的成像策略来监测有害的突触外NMDAR功能 在公元后。我们的战略需要使用一种新型的正电子发射断层扫描(PET)示踪剂[11C]Me-Nb1，它以 携带GluN2B的NMDAR。到目前为止，[11C]Me-NB1是唯一成功验证的GluN2B PET示踪剂 在幼稚的动物身上，最近在少量健康的受试者中进行了测试。我们的初步研究表明 [11C]Me-NB1-PET非常适合于GluN2B亚基的非侵入性作图，具有良好的靶向亲和力和 不同物种间的选择性。然而，无创性评估GluN2B的分布和表达 尚未在AD患者中进行，明确的证据仍不足以证明潜在的 NMDAR功能障碍与阿尔茨海默病的机制及关系[11C]Me-nb1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 本文的主要工作有：(1)提出了一种动力学建模方法和绝对量化方法，以及/或简化的图解方法。 [11C]Me-NB1可在健康对照中建立；(2)PET定量方法将转化为AD患者 我们预计，[11C]Me-NB1-PET在体外和体内与GluN2B结合的增加与AD- AD患者相关脑区(与对照组相比)；(3)作为概念验证，在转基因AD小鼠模型中，我们 预计[11C]Me-NB1-PET可以直接监控GluN2B的变化，并在 新型阿尔茨海默病疗法。总体影响：谷氨酸诱导的神经毒性在AD中的作用导致NMDAR亚型GluN2B 一个潜在的药物和成像靶点。[11C]Me-NB1-PET不仅可以跟踪GluN2B的变化和测量靶点 在新型AD治疗干预期间的占有率，但也将支持更小、更短的试验，以证明 这一机制还有助于为临床试验选择最佳的患者。

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.