Wednesday, February 5, 2025
2/5/2025
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.
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