Development of a Novel PET Tracer for Imaging Microglial Function in Alzheimer's Disease

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SUMMARY Alzheimer’s disease (AD) is the most common form of dementia and a major cause of death in adults over 65. Unfortunately, advancements in early diagnosis and treatment development have been hindered by a paucity of sensitive biomarkers enabling detection of early, functionally relevant, neuromolecular changes: Although data from genome wide association studies have revealed genes relating to a loss of healthy innate immune function as a major risk factor for AD, there remains a need for biomarkers to investigate neuro-immune function preceding and during the development of this disease. Positron Emission Tomography (PET) is an extremely sensitive molecular imaging modality well suited to studying such biomarkers, with established utility for non- invasive in vivo interrogation of biochemical processes. Existing PET biomarkers of neuroinflammation (e.g., the translocator protein 18 kDa [TSPO], CB2, CSF1R, P2X7) suffer from significant drawbacks including a poorly elucidated functional role and/or expression across multiple cell types in the central nervous system (CNS). Within the CNS, the adenosine diphosphate receptor P2Y12R is expressed exclusively on microglia, the innate immune effector cells of the CNS, and drives chemotaxis and morphological changes associated with microglial activation. Generally considered a biomarker of homeostatic microglia, P2Y12 expression has been demonstrated to decrease in both acute (e.g., lipopolysaccharide challenge) and chronic (e.g., AD) neuroinflammation. Postmortem human brain tissue from advanced AD patients demonstrated a global reduction in P2Y12R expression and a near total absence of P2Y12R expression on microglia surrounding amyloid-beta plaques. Despite being an extremely well characterized pharmacological target, there are currently no CNS-penetrable P2Y12R PET tracers. Aiming to address this unmet need, I identified clinical drug candidate AZD1283 as a promising possible PET tracer. Recently, I devised a strategy to radiolabel this molecule with carbon-11 (t1/2=20.4 min), synthesized [11C]AZD1283 and showed it to be highly stable in vitro in human plasma. Here, I will compare [11C]AZD1283 with TSPO PET tracer [11C]DPA-713 for their ability to measure alterations in microglia in two murine models of neuroinflammation (Aim 1). Additionally, I will assess the translational potential of [11C]AZD1283 through imaging healthy non-human primates and in vitro autoradiography of human AD brain tissue (Aim 2). The experience gained by pursuing these aims will allow me to develop a skillset directly applicable to future independent research developing tracers and therapies that target the immune system. I will conduct this work under the mentorship of Michelle James, PhD, a world expert in neuroinflammation PET, with additional mentorship from Thomas Montine, MD, PhD, the chair of Pathology at Stanford. Their mentorship, in conjunction with the excellent training environment and resources available to me at Stanford, are highly conducive to successful completion of this project, and will ultimately enable a successful transition to a career as an innovate and effective independent physician scientist.