Ashworth S, Berges A, Rabiner E A, Wilson A A, Comley R A, Lai R Y K, Boardley R, Searle G, Gunn R N, Laruelle M, Cunningham V J
GlaxoSmithKline Clinical Imaging Centre, London, UK.
Br J Pharmacol. 2014 Mar;171(5):1241-9. doi: 10.1111/bph.12505.
This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H(3) receptors (RO) in healthy human volunteers.
PET scans were obtained after i.v. administration of the H(3) -specific radioligand [(11) C]GSK189254. Each subject was scanned before and after single oral doses of GSK239512, at 4 and 24 h after dose. PET data were analysed by compartmental analysis, and regional RO estimates were obtained by graphical analysis of changes in the total volumes of distribution of the radioligand, followed by a correction for occupancy by the high affinity radioligand. The PK/RO relationship was analysed by a population-modelling approach, using the average PK of GSK239512 during each scan.
Following administration of GSK239512, there was a reduction in the brain uptake of [(11) C]GSK189254 in all regions, including cerebellum. RO at 4 h was higher than at 24 h, and the PK/RO model estimated a PK associated with 50% of RO of 0.0068 ng·mL(-1) . This corresponds to a free concentration of 4.50 × 10(-12 ) M (pK = 11.3).
The affinity of GSK239512 for brain H3 receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in pigs. The study illustrates the utility of carrying out PET studies in humans early in drug development, providing accurate quantification of GSK239512 RO in vivo as a function of time and dose.
本研究旨在调查新型组胺H3受体拮抗剂GSK239512的血浆浓度（PK）与健康人类志愿者大脑中H3受体占有率（RO）之间的关系。
静脉注射H3特异性放射性配体[(11)C]GSK189254后进行PET扫描。每位受试者在单次口服GSK239512剂量前以及给药后4小时和24小时进行扫描。PET数据通过房室分析进行分析，通过对放射性配体分布总体积变化的图形分析获得区域RO估计值，随后对高亲和力放射性配体的占有率进行校正。使用每次扫描期间GSK239512的平均PK，通过群体建模方法分析PK/RO关系。
给予GSK239512后，包括小脑在内的所有区域[(11)C]GSK189254的脑摄取量均降低。4小时时的RO高于24小时时的RO，PK/RO模型估计与50%RO相关的PK为0.0068 ng·mL(-1)。这相当于游离浓度为4.50×10(-12) M（pK = 11.3）。
GSK239512在人体内对脑H3受体的亲和力远高于体外研究预期，且高于在猪身上进行的PET研究中观察到的亲和力。该研究说明了在药物开发早期对人类进行PET研究的实用性，可准确量化GSK239512在体内的RO随时间和剂量的变化。
