Activated macrophages and microglia are key players in the innate response in the pathogenesis of Alzheimer’s disease (AD). They are closely associated with b-amyloid deposits in brains from AD patients and AD mouse models. Emerging evidence revealed that activated microglia/macrophages play dual roles in AD pathogenesis: anti-inflammatory and protective (M2-like) to decrease b-amyloid accumulation by phagocytosis or clearance at the early/preclinical stage, and proinflammatory at the clinical stage. Modulation of macrophages/microglia activation to an anti-inflammatory phenotype has become a promising therapeutic strategy. A noninvasive imaging method to detect the anti-inflammatory macrophages/microglia would enable a better understanding of the key roles these cells play in AD pathogenesis and monitoring of therapeutic effects of potential novel therapies modulating macrophages/microglia phenotype. However, most of the current imaging methods do not distinguish between these different phenotypes (e.g., iron oxide nanoparticles, DFG PET or translocator protein PET), or only target damaging cells (e.g., myeloperoxidase (MPO) imaging), or cannot cross the blood-brain barrier (BBB). Thus, there is an unmet need for a non-invasive imaging method to detect anti-inflammatory microglia/macrophages in AD with the ability to cross the BBB. The mannose receptor (CD206) is a surface marker of M2-like anti-inflammatory macrophages/microglia. In AD, CD206+ microglia closely co-localize with b-amyloid deposits and pathological tau. Anti-inflammatory treatment has been shown to polarize microglia to CD206+ phenotype and reduce b-amyloid accumulation. As such, an imaging probe targeting CD206 could provide a useful tool to track these CD206+ cells noninvasively. We have developed a CD206-specific MRI agent (MannGdFish) that can map and track the changes of CD206+ macrophages in rodent models of wound healing and tumor. However, MannGdFish cannot cross the BBB which limits its application in the brain. We hypothesize that we can develop an [18F]-labeled amphiphilic PET probe with the ability to cross the BBB by conjugating the hydrophilic CD206-targeted binding motif of MannGdFish to hydrophobic lipid chains at different lengths to modulate the hydrophilic/hydrophobic balance and serum affinity. We will evaluate candidate probes’ specificity and the ability to cross the BBB to identify an optimal probe. We will validate the optimal probe by imaging the changes of CD206+ microglia/macrophages in transgenic 5xFAD mice at 2 months (early stage) and 6 months (symptomatic stage), and correlate the imaging data with the water maze test, ex vivo biochemical, flow cytometry and immunohistological results. The output of this proposal will be a novel, highly specific PET probe that can cross the BBB to track CD206+ microglia/macrophages in AD and other neurological diseases. Because of the lower translational cost of PET probes, the results of this work may lead to near-...