Development and assessment of new highly specific PET tracers for imaging innate immune activation in Alzheimer's disease - SUMMARY Alzheimer’s disease (AD) is the most common form of dementia and the fifth leading cause of death among older adults in the United States. Unfortunately, available Food and Drug Administration (FDA)-approved therapeutics for treating AD only offer limited efficacy, largely due to our incomplete understanding of the underlying mechanisms that cause and drive the disease. Genome-wide association studies and immunohistochemistry both implicate neuroinflammation and immune dysfunction as key drivers of AD pathogenesis, but the availability of specific biomarkers to investigate and track the spatiotemporal dynamics and functional phenotypes of 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, in vivo interrogation of biochemical processes. Existing PET biomarkers of neuroinflammation (e.g., the 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. To address this unmet need, we identified G protein-coupled receptor 84 (GPR84) as a promising biomarker of pro-inflammatory innate immune responses in the context of AD. Specifically, my preliminary data showed that GPR84 expression is significantly upregulated in human myeloid cells following pro-inflammatory stimulation and in rodents after lipopolysaccharide challenge; upregulation is also observed in the brains of the 5xFAD AD mouse model. Excitingly, we developed two lead GPR84-specific PET radiotracers, [11C]GLPG-38 and [18F]MGX-110S, that cross the blood-brain barrier (BBB) in healthy rodents and enable sensitive detection of harmful inflammatory immune responses in vivo. In this proposal, I aim to evaluate the sensitivity and specificity of our two novel GPR84-PET radiotracers for quantifying pro-inflammatory immune responses in human cells and a mouse model of systemic and neuroinflammation (Aim 1). I will also assess radiotracer performance in the 5xFAD mouse model of AD and analyze the spatial overlap between radiotracer binding and immune cell markers in human AD postmortem brain tissues from multiple disease stages compared to healthy controls, employing in vitro autoradiography and advanced spatial biology techniques to further establish translational potential of each radiotracer (Aim 2). Successful completion of these aims will result in characterization of two novel GPR84-PET radiotracers, assessing their suitability for in vivo imaging of neuroinflammation and the specific innate immune cell populations they target. Ultimately, translation of these innovative PET radiotracers into clinical practice will significantly enhance our understanding of AD pathogenesis, facilitate targeted therapeutic development, and enable precise monitoring of treatment efficacy, ultimately paving the way for improved outcomes for patients with AD.
