Probing neuroinflammation in Alzheimer's disease with NLRP3 PET radiotracers

使用 NLRP3 PET 放射性示踪剂探测阿尔茨海默病的神经炎症

基本信息

批准号：
10659920
负责人：
Shijun Zhang
金额：
$ 189万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659920
关键词：
ADME Study APP-PS1 Advocate Affinity Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Alzheimer’s disease biomarker Animal Disease Models Animal Diseases Apical Award Binding Biodistribution Biologic Characteristic Biological Assay Biological Markers Biological Products Brain C57BL/6 Mouse Cell Death Cells Chemicals Chemistry Clinical Development Diagnosis Disease Drug Kinetics Drug Targeting Enzyme-Linked Immunosorbent Assay Exhibits Family Future Genetic study Goals Grant Human IL18 gene Immune In Vitro Inflammasome Inflammatory Inflammatory Response Injections Interleukin-1 beta Intervention Investigational Drugs Kinetics Knowledge Label Lead Liver Microsomes Macaca Measures Methods Molecular Monitor Mus Natural Immunity Neurodegenerative Disorders Parents Pathologic Pharmaceutical Chemistry Pharmacology Study Pharmacotherapy Physiological Plasma Positron-Emission Tomography Production Property Proteins Public Health Radiochemistry Radiolabeled Recombinants Research Role Site Structure-Activity Relationship Testing Therapeutic Time Tracer Visualization Western Blotting aged analog biological heterogeneity brain tissue candidate identification clinical development cytokine disease diagnosis drug discovery epidemiology study human disease imaging probe improved in silico in vivo inhibitor inhibitor therapy innovation kinetic model marenostrin molecular imaging mouse model multidisciplinary neuroinflammation non-invasive imaging nonhuman primate novel potential biomarker pre-clinical process optimization protein complex radiotracer rational design receptor research clinical testing scaffold screening small molecule small molecule libraries tool uptake

项目摘要

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.

神经炎症是阿尔茨海默氏病（AD）的重要病理之一目前无法治愈的神经退行性疾病。神经炎症在AD中的病理作用是在AD动物模型和AD中，由分子，药物和遗传研究强烈支持患者。因此，一种新颖且有用的神经炎症生物标志物对于帮助疾病很有价值 AD疗法的诊断，目标参与和临床评估。最近，点头的接收器含有3（nlrp3）炎性体的家族pyrin结构域，这是先天免疫的重要组成部分严格调节免疫炎症反应，已指出在AD开发中的关键作用和进展。 NLRP3炎性体的激活负责产生促炎白介素（IL）-1β和IL-18，最终导致炎症反应。那是NLRP3炎性体代表一种新型的神经炎症生物标志物和正电子发射断层扫描（PET）radiotracers，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，我们的团队成功地开发了小分子NLRP3抑制剂（NLRP3I），具有新颖的机制动作（MOA），它通过与其他已知抑制剂的不同位点直接与NLRP3蛋白结合领域。我们的药物发现工作也导致了一个含有> 200种化合物的小分子库具有各种生物学特征。更重要的是，我们在小鼠和非人类隐私的试点宠物研究（NHP）使用我们当前铅NLRP3的11C和18F标记的放射性示例已经显示出理想的大脑摄取，特定结合和鼓励药代动力学（PK）特性。此外，我们的积累结构活性关系（SAR）研究已经确定了脚手架的关键结构特征，以进一步优化。该提议的核心假设是，通过聚焦药物化学策略将提供新颖的PET放射性示例，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。目标的目标应用是成功地识别具有合适PK特性的NLRP3 PET放射性示例，并准备研究新药（IND）促进研究。提出了三个目标来实现我们的目标。在AIM 1中，新确定的铅NLRP3I将在结构上优化，以识别用于放射性标记的候选NLRP3I 并建立复合管道。在AIM 2中，将在鼠标模型中评估选定的PET放射性示踪剂包括用于生物分布的AD小鼠模型，脑摄取和脑组织特异性结合。在AIM 3中，将在NHP中评估顶级候选PET放射性示例的动力学特性。提议研究非常重要，因为我们正在开发新型的PET放射性示例以验证NLRP3为潜在的神经炎症生物标志物，以帮助精确破译 AD开发中的神经炎症，并有助于AD疗法的临床发育。