Neuroinflammation is an essential player in the pathogenesis of Alzheimer’s disease (AD), a devastating neurodegenerative disorder without cure. However, the clinical translation of anti-inflammatory agents to date is not successful, partially due to the lack of reflective neuroinflammation biomarkers. Emerging evidence has suggested a critical role of the NLRP3 inflammasome, an essential component of innate immunity, in the development of AD. Therefore, NLRP3 positron emission tomography (PET) radiotracers represent novel biomarkers to allow for visualization and measurement of inflammatory progression in AD. Recently, we have developed NLRP3 inhibitors with a novel mechanism of action. Notably, our pilot PET/CT studies in mice using an ¹¹C-labeled radiotracer developed from our lead NLRP3 inhibitor already showed moderate brain uptake, displaceable binding, and encouraging pharmacokinetic (PK) properties as a central nervous system (CNS) PET radiotracer. Furthermore, our accumulated structure-activity relationship studies from our previous drug discovery campaign have confirmed that this chemical scaffold can be structurally optimized to improve potency and PK properties. The goal of this application is to optimize the newly identified lead NLRP3 inhibitors and to develop successful CNS NLRP3 PET tracers. Three specific aims are proposed to accomplish the goal. Aim 1 is to establish radiochemistry to radiolabel the selected NLRP3 inhibitors from a NIH U01 funded project and determine their binding specificity in brain tissues. Aim 2 is to test the PET tracers in C57BL/6 and AD mice to identify candidates for studies in non-human primates (NHPs). Aims 3 is to teste the top performing PET tracers in NHPs for their PK properties and specific binding in brain. It is expected that suitable CNS NLRP3 PET tracers will be available as imaging probes to help with clinical evaluation of therapeutic interventions for AD and potentially aiding early diagnosis of AD.