The histamine H-3 receptor is implicated in the pathophysiology of several central nervous system disorders. N-methyl-6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nicotamide (GSK189254) is a highly potent, selective, and brain-penetrant H-3 receptor antagonist. Previous studies in the pig using PET have shown that C-11-GSK189254 uptake in H-3-rich regions of the brain can be blocked by the selective H-3 antagonist ciproxifan. The purpose of the present study was to evaluate C-11-GSK189254 as a PET radioligand for human studies and to determine the dose-receptor occupancy relationship of GSK189254 in the human brain. Methods: Dynamic PET scans were obtained in healthy subjects over 90 min after intravenous administration of approximately 370 MBq of C-11-GSK189254. Blood samples were taken throughout the scans to derive the arterial plasma parent input function. Each subject was scanned twice, either with tracer alone (test-retest) or before and after a single oral dose of GSK189254 (10-100 mu g). Data were analyzed by compartmental analysis, and regional receptor-occupancy estimates were obtained by graphical analysis of changes in the total volumes of distribution (V-T) of the radioligand. Results: C-11-GSK189254 readily entered the brain; its regional brain distribution reflected the known distribution of H-3 receptors, with high binding in the caudate and putamen, intermediate binding in cortical regions, and low binding in the cerebellum. GSK189254 displayed a high receptor affinity, and a marked reduction in V-T was apparent at all the doses tested. The oral dose equaling 50% occupancy of the available receptor sites (ED50) was estimated as 4.33 mu g. Additional data on plasma pharmacokinetics after oral dosing and the plasma free fraction gave a corresponding estimate of the free concentration of GSK189254 required to occupy 50% of the available receptor sites (EC50) (0.011 nM). The test-retest data showed reductions in regional V-T on the second scan in all subjects. A nonlinear compartmental analysis of this effect demonstrated that this reduction was consistent with carryover of a tracer mass dose effect with an estimated in vivo apparent dissociation constant of 0.010 nM, close to the independent estimate of the plasma EC50. Conclusion: C-11-GSK189254 can be used to quantify H-3 receptor availability in humans in vivo using PET but requires high specific activity; the possibility of tracer mass dose effects should be carefully analyzed.
- H-3 receptor
- brain histamine