Unexpectedly high affinity of a novel histamine H3 receptor antagonist, GSK239512, in vivo in human brain, determined using PET

Background and Purpose 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 H3 receptors (RO) in healthy human volunteers. Experimental Approach PET scans were obtained after i.v. a...

Full description

Saved in:

Bibliographic Details
Published in:	British journal of pharmacology 2014-03, Vol.171 (5), p.1241-1249
Main Authors:	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
Format:	Article
Language:	eng
Subjects:	drug development H3 receptors PET study pharmacokinetics receptor occupancy Research Papers
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Background and Purpose 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 H3 receptors (RO) in healthy human volunteers. Experimental Approach PET scans were obtained after i.v. administration of the H3‐specific radioligand [11C]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. Key Results Following administration of GSK239512, there was a reduction in the brain uptake of [11C]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). Conclusions and Implications 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.
ISSN:	0007-1188 1476-5381