Search

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 (p K = 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. [ABSTRACT FROM AUTHOR]

Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the μ-OR sub-type. In a sample of healthy volunteers, we used [11C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50=7.10 ng ml−1) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-β-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption. [ABSTRACT FROM AUTHOR]

The article offers information on the pharmacodynamics of GlaxoSmithKline (GSK) 1521498 in the human brain as viewed using a positron emission tomography and functional magnetic resonance imaging. It states that GSK1521498 reduces radioligand binding, which indicates that it has high chemical attraction in the human brain. It adds that it greatly affects brain areas than naltrexone in weakening reward-related activation.