Novel GluN2BR Radioligand for PET Neuroimaging in Alcohol Use Disorder

PROJECT SUMMARY Alcohol Use Disorder (AUD), a significant therapeutic challenge, disrupts the brain's glutamatergic system. Preclinical evidence shows that chronic alcohol exposure upregulates the expression and function of GluN2B subunit-containing N-methyl-D-aspartate receptors (GluN2BR). Furthermore, the overactivation of GluN2BR in reward-related brain regions is associated with increased alcohol consumption and alcohol seeking behavior. Hence, the selective antagonism of GluN2BR has garnered interest as a therapeutic target. However, the precise role and availability of GluN2BR in people with AUD remain unknown, limiting our ability to harness GluN2BR- specific therapeutic potential. Positron Emission Tomography (PET) imaging holds promise to quantify neuroreceptor adaptation in living people, thereby facilitating therapeutic development. Our proposal addresses this gap by conducting the first-in-human characterization of a novel PET fluorinated radioligand, (S)-[18F]OF- NB1, utilizing its promising pharmacokinetics and specific brain uptake as demonstrated in our preclinical evaluations. The K99 phase of the grant will focus on establishing the imaging properties as well as the test- retest variability of (S)-[18F]OF-NB1 in healthy participants. The R00 phase will expand this research to compare (S)-[18F]OF-NB1 binding in people with AUD compared to healthy controls. In people with AUD, we will perform PET imaging alongside a laboratory alcohol self-administration session to model alcohol-seeking behavior and subsequent heavy drinking. Additionally, we will collect Ecological Momentary Assessment (EMA) data over a 14-day period to accurately assess cravings and alcohol consumption in a naturalistic setting. The relationship between GluN2BR levels and alcohol drinking behavior will be established. The proposed integrative approach holds the potential to elucidate the intricate neurobiology of AUD through the utilization of state-of-the-art PET imaging techniques and innovative behavioral assessments. This research endeavor will significantly contribute to the development of novel and targeted therapeutic interventions. Upon successful completion, this project will advance my expertise in human PET neuroimaging, kinetic modeling, AUD neuropathology, and behavioral assessments, establishing me as an independent researcher in alcohol-related neuroimaging.