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

: Airaksinen AJ, Jablonowski JA, van der Mey M, Barbier AJ, Klok RP, Verbeek J, Schuit R, Herscheid JDM, Leysen JE, Carruthers NI, Lammertsma AA, Windhorst AD

Publisher: ELSEVIER SCIENCE INC

: 2006

: Nuclear Medicine and Biology

: NUCLEAR MEDICINE AND BIOLOGY

: NUCL MED BIOL

: 33

: 6

: 801

: 810

: 10

: 0969-8051

DOI: https://doi.org/10.1016/j.nucmedbio.2006.05.008

The potent histamine H-3 receptor antagonist JNJ-10181457 (1) was successfully labeled with C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28 +/- 8%) and high specific radioactivity (56 +/- 26 GBq/mu mol). The binding of [C-11]1 to H-3 receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [C-11]1 in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H-3 antagonists, JNJ-5207852 (2) and unlabeled Compound (1), in a concentration-dependent manner. The biodistribution of [C-11]1 in rats was measured at 5, 10, 30 and 60 min. The uptake of [C-11]1 in regions rich in H-3 receptors was highest at 30 min, giving 0.98%, 1.41%, 1.28% and 1.72% dose/g for the olfactory bulb, hippocampus, striaturn and cerebral cortex, respectively. However, the binding of [C-11]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 [C-11]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/6H(3)(-/-) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [C-11]1 could not specifically label H-3 receptors in rodent brain in vivo. Possible causes are discussed. (c) 2006 Elsevier Inc. All rights reserved.