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

Abstract

BACKGROUND AND PURPOSEThis 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 APPROACHPET scans were obtained after i.v. administration of the H3-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. KEY RESULTSFollowing 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 . This corresponds to a free concentration of 4.50 × 10 −12 M (pK = 11.3). CONCLUSIONS AND IMPLICATIONSThe 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. Abbreviations

Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study

“…Previous clinical studies have indicated that GSK239512 is well tolerated as a monotherapy when titrated up to 80 µg, resulting in >90% H 3 receptor occupancy in the brain at trough plasma concentrations [6, 7, 9]. GSK239512 promotes OPC differentiation in vitro and enhances remyelination in the cuprizone mouse model of remyelination [4].…”

Imaging in Central Nervous System Drug Discovery

“…Target engagement (or occupancy studies), which utilise a PET biomarker and varying doses of the drug under investigation, provide some of the most valuable decision making data that can be acquired as part of a FTIH Phase I study [17][18][19][20][21][22][23][24].…”

Remyelinating Pharmacotherapies in Multiple Sclerosis

“…The remyelinating properties of this second antihistamine, a selective, orally bioavailable, and CNS-penetrant H 3 receptor antagonist/inverse agonist originally developed to treat schizophrenia and Alzheimer's disease, were investigated based on proprietary screens separate from those discussed above. GSK239512 was well tolerated and with good CNS penetrance (> 90% H 3 receptor occupancy in the brain, at trough plasma concentrations) [72][73][74].…”