Probing neuroinflammation in Alzheimer's disease with NLRP3 PET radiotracers

神经炎症是阿尔茨海默病（AD）的主要病理之一， 神经退行性疾病目前无法治愈。神经炎症在AD中的病理作用是 在AD动物模型和AD中的分子、药理学和遗传学研究的有力支持 患者因此，一个新的和有用的生物标志物的神经炎症将是有价值的，以帮助疾病 AD治疗剂的诊断、靶点接合和临床评价。最近，NOD样受体 家族pyrin结构域3（NLRP 3）炎性体，先天免疫的必需组分， 紧密调节免疫炎症反应，已表明在AD发展中起关键作用， 进展NLRP 3炎性体的激活负责促炎因子的产生。 白细胞介素（IL）-1β和IL-18，最终导致炎症反应。因此，NLRP 3炎性体 代表一种新的神经炎症生物标志物，以及正电子发射断层扫描（PET）放射性示踪剂， 靶向这种蛋白质复合物将是帮助监测AD炎症进展的重要工具。最近， 我们的团队已经成功地开发了小分子NLRP 3抑制剂（NLRP 3 is）， 作用（MOA），其通过与其他已知抑制剂不同的位点直接结合NLRP 3蛋白， 外地我们的药物发现工作也导致了一个包含超过200种化合物的小分子库 具有各种生物学特性。更重要的是，我们在小鼠和非人类灵长类动物中的试验性PET研究 （NHP）使用11 C-和18F-标记的放射性示踪剂，我们目前的铅NLRP 3 is已经显示出理想的大脑 吸收、特异性结合和令人鼓舞的药代动力学（PK）性质。此外，我们积累的 构效关系（SAR）研究已经确定了支架的关键结构特征，用于进一步研究。 优化.这个建议的中心假设是，我们的领导NLRP 3的结构优化是通过 集中的药物化学策略将提供新的PET放射性示踪剂，可用于定量 测量和区分临床前AD动物模型中的神经炎症状态。这个目标 应用是成功鉴定具有合适PK性质的NLRP 3 PET放射性示踪剂，并为 研究性新药（IND）启动研究。为实现我们的目标，提出了三个目标。在目标1中， 将对新鉴定的前导NLRP 31进行结构优化，以鉴定用于放射性标记的候选NLRP 31 建立复合管道。在目标2中，将在小鼠模型中评价选定的PET放射性示踪剂 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， 将在NHP中评价最佳候选PET放射性示踪剂的动力学性质。拟议 研究是非常重要的，因为我们正在开发新的PET放射性示踪剂，以验证NLRP 3作为 潜在的神经炎症生物标志物，以帮助精确破译的病理贡献， 本发明的目的是提供AD发展中的神经炎症的研究，并帮助AD治疗剂的临床开发。

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.