Blockade of the brain histamine H3 receptor by JNJ-39220675: preclinical PET studies with [¹¹C]GSK189254 in anesthetized baboon.
Blockade of the brain histamine H3 receptor by JNJ-39220675: preclinical PET studies with [¹¹C]GSK189254 in anesthetized baboon.
复制标题
JNJ-39220675 阻断大脑组胺 H3 受体：在麻醉狒狒中使用 [11C]GSK189254 进行临床前 PET 研究。
DOI：
10.1007/s00213-012-2733-x
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发表时间：
2012
影响因子：
3.4
通讯作者：
Fowler,JoannaS
中科院分区：
文献类型：
--
作者：
Logan,Jean;Carruthers,NicholasI;Letavic,MichaelA;Sands,Steven;Jiang,Xiaohui;Shea,Colleen;Muench,Lisa;Xu,Youwen;Carter,Pauline;King,Payton;Fowler,JoannaS
一系列芳氧基吡啶酰胺的临床前表征已鉴别出JNJ-39220675（（4-环丁基-1，4-二氮杂环庚烷-1-基）（6-（4-氟苯氧基）吡啶-3-基）甲酮）作为高亲和力组胺H3受体拮抗剂和进一步药物开发的候选药物，特别是在治疗酒精相关行为方面。方法使用正电子发射断层扫描成像和[11 C] GSK 189254（一种对组胺H3受体具有特异性的可逆高亲和力放射性示踪剂）测量麻醉狒狒在基线时以及静脉注射和经口给予JNJ-39220675（1 mg/kg）后的组胺H3受体利用率。组胺H3受体利用率估计为脑区的总分布体积（VT）。测定了[11 C] GSK 189254结合对注射质量和残留效应的敏感性。静脉内和口服给药后[11 C] GSK 189254结合的阻断率为90%。JNJ-39220675（1 mg/kg）经口给药后，90 min时受体结合率分数>0.9，从90 min至240 min略有增加。与之前的人类研究相似，VT对GSK 189254的质量高度敏感，ED 50估计为0.16 μg/kg。结论JNJ-39220675对[11 C] GSK 189254结合的强效阻断表明，该化合物在低血浆浓度下经口给药后易于穿透血脑屏障并占据组胺H3受体（101纳克/立方厘米）支持进一步开发治疗酒精成瘾和其他疾病的药物。本研究证实了先前报告的[11 C] GSK 189254对剂量>0.1 μg/kg的注射质量具有高灵敏度。
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 H3receptor antagonist and a candidate for further drug development particularly in the treatment of alcohol-related behaviors.ObjectiveThis study measured brain histamine H3receptor 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 H3receptor, was used to measure histamine H3receptor availability at baseline and after i.v. and oral administration of JNJ-39220675 (1 mg/kg) in the anesthetized baboon. Histamine H3receptor 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.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,VTwas highly sensitive to the mass of GSK189254 with ED50estimated 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 H3receptor 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.