Radiosynthesis and biodistribution of a histamine H3 receptor antagonist 4-[3-(4-piperidin-1-yl-but-1-ynyl)-[11C]benzyl]-morpholine: evaluation of a potential PET ligand

The potent histamine H3 receptor antagonist JNJ-10181457 (1) was successfully labeled with 11C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28±8%) and high specific radioactivity (56±26 GBq/μmol). The binding of [11C]1 to H3 receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [11C]1 in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H3 antagonists, JNJ-5207852 (2) and unlabeled Compound (1), in a concentration-dependent manner. The biodistribution of [11C]1 in rats was measured at 5, 10, 30 and 60 min. The uptake of [11C]1 in regions rich in H3 receptors was highest at 30 min, giving 0.98%, 1.41%, 1.28% and 1.72% dose/g for the olfactory bulb, hippocampus, striatum and cerebral cortex, respectively. However, the binding of [11C]1 in the rat brain could not be blocked by pretreatment with either Compound (2) (30 min or 24 h pretreatment) or cold Compound (1) (30-min pretreatment). The biodistribution of [11C]1 in a second species (Balb/c mice) showed a higher overall uptake of the radioligand with an average brain uptake of 8.9% dose/g. In C57BL/6-H3(−/−) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [11C]1 could not specifically label H3 receptors in rodent brain in vivo. Possible causes are discussed.