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. [ 11 C]clozapine, [8-chloro-11-(4-[methyl- 11 C]-methyl-1-piperazinyl)-5 H -dibenzo[b,e]-1,4-diazepine], 1 , an atypical neuroleptic was synthesized by N -methylation of the desmethyl compound norclozapine, 3 , using [ 11 C]methyl iodide or [ 11 C]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/μmol (2.5–3.5 Ci/μmol). 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.