Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET

Sharon Ashworth, Eugenii A Rabiner, Roger N Gunn, Christophe Plisson, Alan A Wilson, Robert A Comley, Robert Y K Lai, Antony D Gee, Marc Laruelle, Vincent J Cunningham

Research output: Contribution to journalArticlepeer-review

65 Citations (Scopus)


The histamine H3 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 H3 receptor antagonist. Previous studies in the pig using PET have shown that 11C-GSK189254 uptake in H3-rich regions of the brain can be blocked by the selective H3 antagonist ciproxifan. The purpose of the present study was to evaluate 11C-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 11C-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 μg). Data were analyzed by compartmental analysis, and regional receptor-occupancy estimates were obtained by graphical analysis of changes in the total volumes of distribution (VT) of the radioligand.

Results: 11C-GSK189254 readily entered the brain; its regional brain distribution reflected the known distribution of H3 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 VT was apparent at all the doses tested. The oral dose equaling 50% occupancy of the available receptor sites (ED50) was estimated as 4.33 μg. 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 VT 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: 11C-GSK189254 can be used to quantify H3 receptor availability in humans in vivo using PET but requires high specific activity; the possibility of tracer mass dose effects should be carefully analyzed.
Original languageEnglish
Pages (from-to)1021-1029
Number of pages9
JournalJournal of Nuclear Medicine
Issue number7
Publication statusPublished - Jul 2010


Dive into the research topics of 'Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET'. Together they form a unique fingerprint.

Cite this