title: Synthesis of n.c.a. carbon-11 labelled clozapine and its major metabolite clozapine-N-oxide and comparison of their biodistribution in mice.
abstract: N.c.a. [11C]clozapine, [8-chloro-11-(4-[methyl-11C]-methyl-1-piperazinyl)-5H-dibenzo[b,e]-1, 4-diazepine], 1, an atypical neuroleptic was synthesized by N-methylation of the desmethyl compound norclozapine, 3, using [11C]methyl iodide or [11C]methyl triflate for comparison. Subsequent oxidation of 1 with m-chloroperoxybenzoic acid yielded clozapine-N-oxide, 2, the major metabolite of 1. Purification of both radiolabelled products was carried out using a combined semi-preparative HPLC/solid phase extraction procedure. In preparative scale runs overall radiochemical yields for 1 and 2 were 70 and 65%, respectively. The radiochemical purities of both compounds exceeded 98% and the specific activities were in the range of 92-130 GBq/mumol (2.5-3.5 Ci/mumol). Biodistribution of 1 and 2 has been studied in NMRI mice. 10 min p.i. clozapine shows a 24-fold higher brain uptake than its major metabolite. At 60 min p.i., however, the cerebral uptake of both compounds is almost identical.
authors.affiliation: Institut für Nuklearchemie, Forschungszentrum Jülich GmbH, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Bender
authors.forename: M
authors.initials: M
authors.lastname: Holschbach
authors.forename: G
authors.initials: G
authors.lastname: Stöcklin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D005260:Female; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D003024:Clozapine; C079149:clozapine N-oxide