Project Summary Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing the endogenous cannabinoid ligand: 2- arachidonylglycerol (2-AG). Inhibition of MAGL, not only increases 2-AG levels, resulting in activation of the endocannabinoid system (eCB), but also reduces levels of arachidonic acid (AA), a pain and inflammation-inducing prostaglandin precursor. This unique synergetic effect provides protection against neuroinflammation and neurodegenerative diseases. Genetic ablation of MAGL has also resulted in an attenuation of neuroinflammation, for example, a substantial reduction of amyloid plaques in transgenic mouse model of Alzheimer’s disease (AD). In autopsy brains of Alzheimer’s patients, MAGL levels in nucleus basalis are 600-800% higher than that of normal brain, and showed a positive correlation (R = 0.8) between enzyme expression levels and AD Braak stage (I-VI). In the past, remarkable advances have been made in the understanding of MAGL and its modulation at the molecular level in neurodegenerative diseases via ex vivo (destructive) analysis, which, by definition, cannot be directly translated to most human tissues in vivo. In this context, positron emission tomography (PET) is a noninvasive molecular imaging tool that can provide such information via targeted radioactive molecules (radiotracers) with exquisite sensitivity, which will be highly advantageous in monitoring disease progression and treatment response. The radiotracer [11C]SAR127303 (abbreviated as [11C]SAR127), developed by the PI, can fill this void and provide a quantitative tool for measuring MAGL activity and possible aberrant eCB function in AD. Our preliminary studies show that [11C]SAR127 is a specific and brain penetrant PET radiotracer that is consistent with the distribution of MAGL in the brain. In this application, we aim to evaluate [11C]SAR127 for its ability to track MAGL changes in vivo to monitor disease progression in transgenic AD mouse models, evaluate target engagement and assess treatment response to MAGL-related pharmacotherapies. This work will represent the first PET biomarker study measuring changes of a potentially disease-modifying enzyme MAGL in the AD progression and treatment. We expect that this proposed work will not only help us to differentiate symptomatic from true neuroprotective response via MAGL inhibition, but also contribute to the development of MAGL-based therapeutic interventions to improve quality of life of AD patients. Relevance: This proposal has the potential to improve public health and help patients suffering from Alzheimer’s disease through the discovery of novel neurotherapeutics using MAGL PET ligands.