Abstract
RationaleThe 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.ObjectiveThis study measured brain histamine H3 receptor blockade by JNJ-39220675 (1 mg/kg) in the female baboon.MethodsPositron 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 (V T) in brain regions. The sensitivity of [11C]GSK189254 binding to injected mass and carryover effects was determined.ResultsJNJ-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, V T was highly sensitive to the mass of GSK189254 with ED50 estimated to be 0.16 μg/kg.ConclusionsThe 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.
Highlights
Histamine is synthesized in histaminergic neurons which are localized in the tuberomamillary nucleus in the posterior hypothalamus and project widely throughout the central nervous system (Brown et al 2001)
Histamine H3 receptors have been identified as presynaptic autoreceptors on histamine neurons where they negatively regulate histamine release, thereby modulating histaminergic tone (Hill et al 1997; Arrang et al 1983)
We examined the effect of specific activity of [11C]GSK189254 on baseline measures of histamine H3 receptor availability in order to account for tracer mass and carryover effects
Summary
Histamine is synthesized in histaminergic neurons which are localized in the tuberomamillary nucleus in the posterior hypothalamus and project widely throughout the central nervous system (Brown et al 2001). The histamine H3 receptor is one of four histamine receptor subtypes (Hill et al 1997). Histamine H3 receptors have been identified as presynaptic autoreceptors on histamine neurons where they negatively regulate histamine release, thereby modulating histaminergic tone (Hill et al 1997; Arrang et al 1983). The H3 receptor is a presynaptic heteroreceptor in nonhistaminecontaining neurons in both the central and peripheral nervous systems. Nonhistamine-containing neurons modulated by the H3 receptor utilize a variety of neurotransmitters including
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