Project Summary: Strong epidemiological evidence linking schizophrenia (SCZ) and cannabis suggests that the endocannabinoid (eCB) system plays a key role in the pathophysiology of the disease. Early cannabis use increases the risk of developing SCZ by almost twofold, making cannabis a strong risk factor for SCZ [59,60], acting through an unknown molecular mechanism. Understanding the neuropathology of the early course of SCZ such as First Episode Psychosis (FEP) and the state of clinical high risk (CHR) that precedes FEP is critically needed to identify new therapeutic targets for prevention and treatment. Fatty acid amide hydrolase (FAAH) is the enzyme responsible for the metabolism of eCBs such as anandamide (AEA) setting the tone of the eCB, tightly regulating brain levels. In humans, dramatic elevations (up to eightfold) of AEA were detected in cerebrospinal fluid (CSF) of SCZ and first episode psychosis (FEP) [91,92], and importantly in CHR [136], suggesting the presence of altered eCB metabolism (reduced FAAH) early in the course of SCZ, including its high risk states. However, no study has investigated FAAH, the eCB gatekeeping enzyme, in-vivo in brain in FEP or CHR, and its relationship with behavior and cognition is currently unknown. Our team has synthesized [11C]CURB and demonstrated its excellent properties for selective and reliable PET brain imaging of FAAH [172]. We also established the safety, validation and dosimetry of [11C]CURB as well as its reproducible quantifiability [177,179]. Thus, the overall aim of our proposal is to use [11C]CURB to image the eCB enzyme FAAH using PET with a high-resolution research tomograph (HRRT) in antipsychotic-free patients with FEP and CHR. One hundred and fifty participants (n=50 FEP, n=50 CHR and n=50 HV) will be included to test our hypothesis. This study will help us understand a) whether there are changes in FAAH in the early course of disease (FEP<CHR<HV), b) explore for the first time the role of brain FAAH in behavior and cognition. We believe this study will provide novel treatment targets (i.e. FAAH to regulate eCBs) to treat or perhaps even delay or abort transition to SCZ in those at risk. Our preliminary [11C]CURB data in FEP, CHR and HV suggest the first evidence of reduced AEA metabolism (reduced brain FAAH) early in the course of disease consistent with our hypothesis (FEP<CHR<HV), and congruent with our preliminary data in (treated) SCZ patients. The PI and her colleagues have a considerable track record of performing complex molecular PET imaging studies in FEP and CHR subjects [65,181-184]. The high resolution PET scanner, well characterized radiotracer and the infrastructure for neurobiological research in CHR and FEP are novel aspects of the project that will provide a fundamental basis for future studies of pharmacologic interventions in CHR and FEP focused on eCB to treat FEP or even prevent SCZ in CHR.