title: 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.
abstract: The potent histamine H(3) receptor antagonist JNJ-10181457 (1) was successfully labeled with (11)C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28+/-8%) and high specific radioactivity (56+/-26 GBq/mumol). The binding of [(11)C]1 to H(3) receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [(11)C]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 [(11)C]1 in rats was measured at 5, 10, 30 and 60 min. The uptake of [(11)C]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, striatum and cerebral cortex, respectively. However, the binding of [(11)C]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 [(11)C]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-H(3)(-/-) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [(11)C]1 could not specifically label H(3) receptors in rodent brain in vivo. Possible causes are discussed.
authors.affiliation: Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Anu J
authors.initials: AJ
authors.lastname: Airaksinen
authors.forename: Jill A
authors.initials: JA
authors.lastname: Jablonowski
authors.forename: Margreet
authors.initials: M
authors.lastname: van der Mey
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Barbier
authors.forename: Rob P
authors.initials: RP
authors.lastname: Klok
authors.forename: Joost
authors.initials: J
authors.lastname: Verbeek
authors.forename: Robert
authors.initials: R
authors.lastname: Schuit
authors.forename: Jacobus D M
authors.initials: JD
authors.lastname: Herscheid
authors.forename: Josee E
authors.initials: JE
authors.lastname: Leysen
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C515396:4-(3-(4-piperidin-1-ylbut-1-ynyl)benzyl)morpholine; D002250:Carbon Radioisotopes; D006633:Histamine Antagonists; D008024:Ligands; D009025:Morpholines; D010880:Piperidines; D019275:Radiopharmaceuticals; D018100:Receptors, Histamine H3