Inflammation and immune dysfunction have emerged as key drivers of Alzheimer’s disease (AD) initiation and progression, but the availability of sensitive biomarkers to investigate and track immune cells in AD remains extremely limited. Positron Emission Tomography (PET) is a highly sensitive molecular imaging modality well-suited for the longitudinal study of such biomarkers, with demonstrated utility for non-invasive detection of biochemical processes. Existing PET biomarkers of neuroinflammation (e.g., gold standard: translocator protein 18kDa; TSPO) suffer from significant drawbacks, including non-specific expression across multiple cell types in the central nervous system (CNS) and an inability to distinguish between beneficial and harmful inflammatory processes. We identified G-protein-coupled receptor 84 (GPR84) as a promising biomarker of pro-inflammatory immune responses in the context of AD. Importantly, we have shown that GPR84 is significantly increased in human cells after a harmful inflammatory stimulus and in the brain of an AD mouse model (known as 5xFAD). Excitingly, we have developed two lead GPR84-specific PET tracers that cross the blood-brain barrier in healthy rodents and enable detection of harmful immune responses in living subjects. In this proposal, we aim to evaluate the sensitivity and specificity of our two lead GPR84-PET tracers for quantifying pro-inflammatory immune responses in human cells and a mouse model of systemic/neuro-inflammation (Aim 1). The tracers will also be assessed in the 5xFAD mouse model of AD and in human AD postmortem brain tissue across multiple disease stages versus healthy controls (Aim 2). Completion of these aims will result in characterization of the first GPR84-PET tracers suitable for in vivo PET imaging of neuroinflammation, with high potential for advancing understanding and treatment of AD.