Unexpectedly high affinity of a novel histamine H(3) receptor antagonist, GSK239512, in vivo in human brain, determined using PET.

Background and PurposeThis study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H-3 receptor antagonist, GSK239512, and the brain occupancy of H-3 receptors (RO) in healthy human volunteers. Experimental ApproachPET scans were obtained after i.v. administration of the H-3-specific radioligand [C-11]GSK189254. Each subject was scanned before and after single oral doses of GSK239512, at 4 and 24h 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. Key ResultsFollowing administration of GSK239512, there was a reduction in the brain uptake of [C-11]GSK189254 in all regions, including cerebellum. RO at 4h was higher than at 24h, and the PK/RO model estimated a PK associated with 50% of RO of 0.0068ngmL(-1). This corresponds to a free concentration of 4.50 x 10(-12)M (pK = 11.3). Conclusions and ImplicationsThe affinity of GSK239512 for brain H-3 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 ROin vivo as a function of time and dose.