Blockade of the brain histamine h3 receptor by jnj-39220675: Preclinical pet studies with [11C]gsk189254 in anesthetized baboon

Rationale The preclinical characterization of a series of aryloxypyridine amides has identified JNJ-39220675 ((4- cyclobutyl-1,4-diazepan-1-yl)(6-(4- fluorophenoxy)pyridin- 3-yl)methanone) as a high-affinity histamine H3 receptor antagonist and a candidate for further drug development particularly in the treatment of alcohol-related behaviors. Objective This study measured brain histamine H3 receptor blockade by JNJ-39220675 (1 mg/kg) in the female baboon. Methods Positron emission tomography imaging and [11C] GSK189254, a reversible high-affinity radiotracer with specificity for the histamine H3 receptor, was used to measure histamine H3 receptor availability at baseline and after i.v. and oral administration of JNJ-39220675 (1 mg/kg) in the anesthetized baboon. Histamine H3 receptor availability was estimated as the total distribution volume (VT) in brain regions. The sensitivity of [11C]GSK189254 binding to injected mass and carryover effects was determined. Results JNJ-39220675 produces robust (ca. 90 %) blockade of [11C]GSK189254 binding after i.v. and oral administration. After oral administration of JNJ-39220675 (1 mg/kg), the fractional receptor occupancy was >0.9 at 90 min with a slight increase from 90 to 240 min. Similar to prior studies in humans, VT was highly sensitive to the mass of GSK189254 with ED50 estimated to be 0.16 μg/kg. Conclusions The robust blockade of binding of [11C] GSK189254 by JNJ-39220675 demonstrates that this compound readily penetrates the blood-brain barrier and occupies the histamine H3 receptor after oral administration at low plasma concentrations (~1 ng/cc) supporting further drug development for alcohol addiction and other disorders. This study corroborates prior reports of the high sensitivity of [11C]GSK189254 to injected mass at doses >0.1 μg/kg.