Probing neuroinflammation in Alzheimer's disease with NLRP3 PET radiotracers

神经炎是阿尔茨海默病(AD)的主要病理之一，是一种 目前尚无治愈的神经退行性疾病。神经炎症在AD中的病理作用是 得到了AD动物模型和AD的分子、药理学和遗传学研究的有力支持 病人。因此，一种新的、有用的神经炎症生物标志物将对疾病有帮助。 阿尔茨海默病治疗的诊断、目标参与和临床评估。最近，NOD样受体 含有3(NLRP3)炎症体的家族比林结构域，是天然免疫的基本成分， 严密调节免疫炎症反应，已被证明在AD的发生和发展中起关键作用 进步。NLRP3炎症体的激活负责促炎因子的产生 白介素1β和白介素18，最终导致炎症反应。因此，NLRP3炎症体 代表了一种新的神经炎症生物标记物和正电子发射断层扫描(PET)放射示踪剂 靶向这种蛋白复合体将是帮助监测AD炎症进展的重要工具。最近， 我们的团队已经成功地开发出小分子NLRP3抑制剂(NLRP3is)，其新的机制是 作用(MOA)，它通过与其他已知的抑制剂不同的位置直接与NLRP3蛋白结合 田野。我们的药物发现工作还导致了一个含有&gt；200化合物的小分子资料库 具有各种生物学特性。更重要的是，我们在老鼠和非人类灵长类动物中进行的PET试验研究 (NHP)使用我们目前的铅NLRP3的11C和18F标记的放射性示踪剂已经显示出理想的大脑 摄取、特定结合和激励性药代动力学(PK)特性。此外，我们积累了 结构-活性关系(SAR)研究确定了支架的关键结构特征，以便进一步 优化。这一提议的中心假设是，我们领先的NLRP3的结构优化是通过 聚焦药物化学策略将提供可用于定量检测的新型PET放射性示踪剂 测量和区分临床前AD动物模型中的神经炎症状态。这样做的目的是 应用是成功地识别具有合适PK性质的NLRP3 PET放射性示踪剂，并为 研究性新药(IND)使研究成为可能。为了实现我们的目标，我们提出了三个目标。在目标1中， 新确定的先导NLRP3将在结构上进行优化，以确定用于放射性标记的候选NLRP3 建设复合型管道。在AIM 2中，选定的PET放射性示踪剂将在小鼠模型中进行评估 包括AD小鼠模型的生物分布、脑摄取和脑组织中的特异性结合。在《目标3》中， 首选的PET放射性示踪剂将在NHP中进行动力学性质的评估。建议数 研究意义重大，因为我们正在开发新的PET放射性示踪剂，以验证NLRP3作为一种 潜在的神经炎症生物标记物，帮助准确破译 神经炎症在阿尔茨海默病的发展，并协助临床开发的阿尔茨海默病的治疗方法。

Neuroinflammation is one of the prominent pathologies of Alzheimer’s disease (AD), a neurodegenerative disorder without cure currently. The pathological roles of neuroinflammation in AD are strongly supported by molecular, pharmacological, and genetic studies in AD animal models and in AD patients. Therefore, a novel and useful biomarker of neuroinflammation would be valuable to aid disease diagnosis, target engagement, and clinical evaluations of AD therapeutics. Recently, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, an essential component of innate immunity that tightly regulates the immune inflammatory responses, has been indicated critical roles in AD development and progression. Activation of the NLRP3 inflammasome is responsible for the production of pro-inflammatory interleukin (IL)-1β and IL-18, ultimately leading to inflammatory responses. Thus, NLRP3 inflammasome represents a novel neuroinflammation biomarker, and positron emission tomography (PET) radiotracers that target this protein complex would be important tools to help monitor inflammatory progression in AD. Recently, our team has successfully developed small molecule NLRP3 inhibitors (NLRP3is) with a novel mechanism of action (MOA), which is directly binding to the NLRP3 protein via a distinct site from other known inhibitors in the field. Our drug discovery efforts have also led to a library of small molecules containing > 200 compounds with various biological characteristics. More importantly, our pilot PET studies in mice and non-human primates (NHPs) using 11C- and 18F-labeled radiotracers of our current lead NLRP3is already showed desirable brain uptake, specific binding, and encouraging pharmacokinetic (PK) properties. Furthermore, our accumulated structure-activity relationship (SAR) studies have identified key structural features of the scaffolds for further optimization. The central hypothesis of this proposal is that structural optimization of our lead NLRP3is by focused medicinal chemistry strategies will provide novel PET radiotracers that can be used to quantitatively measure and differentiate neuroinflammation status in preclinical AD animal models. The goal of this application is to successfully identify NLRP3 PET radiotracers with suitable PK properties and prepare for investigational new drug (IND) enabling studies. Three aims are proposed to achieve our objectives. In Aim 1, the newly identified lead NLRP3is will be structurally optimized to identify candidate NLRP3is for radiolabeling and building up compound pipeline. In Aim 2, selected PET radiotracers will be evaluated in mouse models including an AD mouse model for biodistribution, brain uptake and specific binding in brain tissues. In aim 3, the top candidate PET radiotracers will be evaluated in NHPs for their kinetic properties. The proposed research is highly significant because we are developing novel PET radiotracers to validate NLRP3 as a potential neuroinflammation biomarker, to help precisely decipher the pathological contributions of neuroinflammation in AD development, and to aid clinical development of AD therapeutics.