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- Title
Blockade of the brain histamine H3 receptor by JNJ-39220675: preclinical PET studies with [C]GSK189254 in anesthetized baboon.
- Authors
Logan, Jean; Carruthers, Nicholas; Letavic, Michael; Sands, Steven; Jiang, Xiaohui; Shea, Colleen; Muench, Lisa; Xu, Youwen; Carter, Pauline; King, Payton; Fowler, Joanna
- Abstract
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 H receptor antagonist and a candidate for further drug development particularly in the treatment of alcohol-related behaviors. Objective: This study measured brain histamine H receptor blockade by JNJ-39220675 (1 mg/kg) in the female baboon. Methods: Positron emission tomography imaging and [C]GSK189254, a reversible high-affinity radiotracer with specificity for the histamine H receptor, was used to measure histamine H receptor availability at baseline and after i.v. and oral administration of JNJ-39220675 (1 mg/kg) in the anesthetized baboon. Histamine H receptor availability was estimated as the total distribution volume ( V) in brain regions. The sensitivity of [C]GSK189254 binding to injected mass and carryover effects was determined. Results: JNJ-39220675 produces robust (ca. 90 %) blockade of [C]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 was highly sensitive to the mass of GSK189254 with ED estimated to be 0.16 μg/kg. Conclusions: The robust blockade of binding of [C]GSK189254 by JNJ-39220675 demonstrates that this compound readily penetrates the blood-brain barrier and occupies the histamine H 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 [C]GSK189254 to injected mass at doses >0.1 μg/kg.
- Subjects
HISTAMINE; POSITRON emission tomography; BABOONS as laboratory animals; ANESTHETICS; DRUG development; BLOOD-brain barrier
- Publication
Psychopharmacology, 2012, Vol 223, Issue 4, p447
- ISSN
0033-3158
- Publication type
Article
- DOI
10.1007/s00213-012-2733-x