C-11-GSK189254: A Selective Radioligand for In Vivo Central Nervous System Imaging of Histamine H-3 Receptors by PET

The histamine H-3 receptor is a G-protein-coupled presynaptic auto- and heteroreceptor whose activation leads to a decrease in the release of several neurotransmitters including histamine, acetycholine, noradrenaline, and dopamine. H-3 receptor antagonists such as 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) can increase the release of these neurotransmitters and thus may offer potential therapeutic benefits in diseases characterized by disturbances of neurotransmission. The aim of this study was to synthesize and evaluate C-11-labeled GSK189254 (C-11-GSK189254) for imaging the histamine H-3 receptor in vivo by PET. Methods: GSK189254 exhibits high affinity (0.26 nM) and selectivity for the human histamine H-3 receptor. Autoradiography experiments were performed using H-3-GSK189254 to evaluate its in vitro binding in porcine brain tissues. GSK189254 was labeled by N-alkylation using C-11-methyl iodide in good yields, radiochemical purity, and specific activity. A series of PET experiments was conducted to investigate C-11-GSK189254 binding in the porcine brain. Results: In vitro autoradiography demonstrated specific H-3-GSK189254 binding in the porcine brain; therefore, C-11-GSK189254 was evaluated in vivo in pigs and showed good brain penetration and high uptake in regions such as the striatum and cortices, known to contain high densities of the histamine H-3 receptors. The radioligand kinetics were reversible, and quantitative analysis was achieved with a 2-tissue-compartmental model yielding the distribution volume as the outcome measure of interest. The distribution volume was reduced to a homogeneous level in all regions after blocking by the coadministration of either unlabeled GSK189254 or ciproxifan, a structurally distinct histamine H-3 antagonist. Further coadministration studies allowed for the estimation of the radioligand affinity (0.1 nM) and the density of histamine H-3 receptor sites in the cerebellum (0.74 nM), cortex (2.05 nM), and striatum (2.65 nM). Conclusion: These findings suggest that C-11-GSK189254 possesses appropriate characteristics for the in vivo imaging of the histamine H-3 receptor by PET.