A positron emission tomography (PET) radioligand, [18 F]FMH3, has been developed to interrogate histamine receptor subtype 3 (H3R), where dysfunction at this site is linked with obesity, sleep abnormality, and cognitive disorders. [18 F]FMH3 was evaluated for imaging central H3R sites in non-human primates through test-retest (TRT) and dose-receptor occupancy studies with two selective H3R antagonists in order to support clinical investigations. Two adult female baboons underwent [18 F]FMH3 PET brain scans in the HR+, at repeated baseline (n = 7) and following administration of escalating doses of ABT-239 (0.003-0.1m/kg, n = 4) and ciproxifan (0.5-2.1 mg/kg, n = 7). Volume of distribution (VT ) in brain regions was estimated using the 2-tissue compartment model. TRT variability of VT across repeated baseline scans was reported as % coefficient of variation (COV). ABT-239 and ciproxifan occupancy at H3R was estimated using the occupancy plot, and the relationship of occupancy with dose and plasma levels was determined. In baboons, distribution of [18 F]FMH3 was high in the striatum, intermediate in cortical regions, and low in the brain stem. COV of baseline VT was 7.0 ± 3.5%, averaged across regions and animals. Dose-dependent effects of ABT-239 and ciproxifan measured the brain. ED50 and EC50, respectively, were 0.011 mg/kg and 0.942 ng/ml for ABT-239 and 0.73 mg/kg and 208.3 ng/ml for ciproxifan. [18 F]FMH3 demonstrated high TRT reliability and can be used to measure occupancy of H3R-targeted drugs. Validation in non-human primates support [18 F]FMH3 PET studies toward clinical investigations of H3R.

中文翻译：

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用[18 F] FMH3成像组胺H3受体：在非人类灵长类动物中的重新测试和占用率研究。

已开发出一种正电子发射断层扫描（PET）放射性配体[18 F] FMH3来询问组胺受体亚型3（H3R），其中该部位的功能障碍与肥胖症，睡眠异常和认知障碍有关。[18 F] FMH3通过使用两种选择性H3R拮抗剂的重新测试（TRT）和剂量受体占用研究，评估了非人类灵长类动物中中心H3R的成像，以支持临床研究。在重复的基线（n = 7）和给予递增剂量的ABT-239（0.003-0.1m / kg，n = 4）和ciproxifan（HR）后，对两只成年雌性狒狒在HR +中进行[18 F] FMH3 PET脑扫描。 0.5-2.1 mg / kg，n = 7）。使用2组织隔室模型估算大脑区域的分布体积（VT）。VT在重复基线扫描中的TRT变异性报告为变异系数百分比（COV）。使用占有率图估算H3R处的ABT-239和ciproxifan占有率，并确定占有率与剂量和血浆水平的关系。在狒狒中，[18 F] FMH3的分布在纹状体中较高，在皮质区域中居中，而在脑干中较低。基线室速的COV为7.0±3.5％，在各个地区和动物中平均。ABT-239和ciproxifan的剂量依赖性作用可测量大脑。对于ABT-239，ED50和EC50分别为0.011 mg / kg和0.942 ng / ml，对于cipififan为0.73 mg / kg和208.3 ng / ml。[18 F] FMH3具有较高的TRT可靠性，可用于测量以H3R为靶标的药物的占用率。在非人类灵长类动物中的验证支持[18 F] FMH3 PET研究对H3R的临床研究。