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Chronic alcohol use has important effects on the glutamate system. The metabotropic glutamate 5 (mGlu5) receptor has shown promise in preclinical models as a target to reduce drinking-related behaviors and cue-induced reinstatement, motivating human studies of mGlu5 receptor negative allosteric modulators. The goal of this work was to measure levels of mGlu5 receptor availability with positron emission tomography (PET) imaging using the mGlu5 receptor-specific radiotracer [ 18 F]FPEB during early and extended alcohol abstinence. Subjects who met DSM-5 criteria for alcohol use disorder (AUD; n = 17) were admitted inpatient for the study duration. [ 18 F]FPEB PET scans were acquired first during early abstinence (6 ± 4 days after last drink) and a second time during extended abstinence (n = 13; 27 ± 6 days after last drink). A single scan was acquired in healthy controls matched for sex and smoking status (n = 20). [ 18 F]FPEB total volumes of distribution (V T ) corrected for partial volume effects were measured using equilibrium analysis throughout the brain. A linear mixed model controlling for smoking status and sex identified significantly higher [ 18 F]FPEB V T in AUD subjects at early abstinence compared to controls (F (1,32)  = 7.23, p = 0.011). Post-hoc analyses revealed this effect to occur in cortical brain regions. No evidence for significant changes in [ 18 F]FPEB V T over time were established. These findings provide human evidence consistent with a robust preclinical literature supporting mGlu5 receptor drugs as pharmacotherapies for AUD.

Longitudinal imaging of metabotropic glutamate 5 receptors during early and extended alcohol abstinence