[18F]MK-9470-PET imaging of cerebral CB1 receptor as a non-invasive biomarker for the diagnosis and staging of hepatic encephalopathy

Hepatic encephalopathy (HE) is a devastating neuropsychiatric complication of acute and chronic liver failure, yet objective and translatable biomarkers for quantifying brain involvement and staging disease progression remain limited. Given the growing evidence implicating the endocannabinoid system—particularly cerebral cannabinoid receptor type 1 (CB1R)—in liver failure–induced brain dysfunction, here we evaluated the established CB1R-targeted PET radioligand [ 18 F]MK-9470 for its ability to noninvasively quantify and stage HE in vivo . Using two complementary murine models of HE, we performed dynamic [ 18 F]MK-9470 PET to measure regional brain uptake and retention, and integrated imaging readouts with liver histology/biochemistry and cerebral edema–related assessments. [ 18 F]MK-9470 PET revealed progressively increased brain tracer uptake and retention with HE severity in both models, with prominent signal enhancement in cortical and hippocampal regions. In parallel, HE mice exhibited AQP4 upregulation, increased brain water content, and rising plasma ammonia, accompanied by elevated hippocampal CB1R mRNA/protein expression and increased CB1 immunoreactivity. Across the full disease course, cerebral [ 18 F]MK-9470 exposure (AUC) correlated strongly with indices of liver injury/fibrosis and with cerebral edema markers. Collectively, these results identify CB1R upregulation as a quantitative imaging signature of HE progression and support [ 18 F]MK-9470 PET as a noninvasive, sensitive, and clinically translatable platform for HE diagnosis and staging.