IN VIVO ALTERATIONS IN BRAIN GLUCOSE UTILIZATION WITH RVT-101, A 5HT6 INHIBITOR FOR THE TREATMENT OF ALZHEIMER’S DISEASE

Abstract

RVT-101 is a potent antagonist of the 5-hydroxytryptamine 6 (5-HT6) serotonin receptor. Reduced glucose utilization is an early sign of decreasing brain function in AD. Altered neuronal glucose uptake assessed by flurodeoxyglucose-positron emission tomography (FDG-PET) may be useful as a diagnostic foundation for identifying patients with AD. This study evaluates RVT-101 at clinically relevant doses on healthy rat brain glucose utilization using FDG-PET/CT. Healthy, young CD rats were pre-dosed with placebo or RVT-101 (10 mg/kg or 20 mg/kg) 3 h prior to FDG (18.1 ± 3.5 MBq, i.v.). Brain FDG standard uptake values (SUV) were quantified using scanning in single 20 min list mode (BioPET/CT, Sedecal) starting 30 min post FDG dosing. PET/CT scans were analyzed as a single time frame summarizing counts over 20 min. All experiments were completed in an accredited facility according to NIH guidelines. PET/CT imaging data were analyzed using Student’s t-test, cluster analysis, and multivariate analysis of variance (MANOVA) using a subset of SUV from 5 cluster-identified regions. RVT-101 increased glucose uptake in healthy young CD rats in a dose dependent manner in almost all brain regions, but pairwise comparisons did not reach statistical significance. SUV from 5 regions that clustered separately were identified: acumbens, cerebellum (white), orbitofrontal cortex, insular cortex and pituitary. Analyzing the composite SUV profile from 5 brain regions in a linear regression model showed a statistically significant overall dose effect (p=0.0006) Further, cluster analysis revealed a placebo outlier, which when removed, provide additional support of a drug effect on glucose uptake in sub-regions. Glucose uptake after pre-treatment with RVT-101 compared to placebo showed a trend of increased glucose uptake in the majority of brain regions analyzed, especially in the 20 mg/kg group. Selection of a subset of regions for regression analysis revealed a statistically significant dose effect related to glucose uptake. These data suggest that RVT-101 may increase brain glucose utilization, an important biologic marker for drugs being developed for AD.