11C-labelling of the analgesic tramadol and its major metabolites by selective O- and N-methylation

For in vivo pharmacokinetic studies with PET, the analgesic Tramadol(1-(3-methoxyphenyl)-2-dimethylaminomethyl-cyclohexan-1-ol) and its major O- and N-desmethylated metabolites M1 and M2 were labelled with carbon-11. Starting with the corresponding desmethyl precursors, (1R, 2R)-(+), (1S, 2S)-(−)-[O-methyl-¹¹C]Tramadol and racemic-[N-methyl-¹¹C]Tramadol were prepared by methylation with n.c.a. [¹¹C]methyl iodide in DMSO with radiochemical yields of 85 and 90%, respectively. Specific n.c.a. N-methylation of bis-desmethyl-Tramadol (M5) was achieved without base obtaining ¹¹C-labelled (1R, 2R)-(+)- and (1S, 2S)-(−)-M1 with 90% radiochemical yield. However, a selective O-methylation of (+)- and (−)-M5 was not possible even with an excess of NaOH, and only 70% of (1R, 2R)-(+)- and (1S, 2S)-(−)-[O-methyl-¹¹C]M2 was obtained. Quaternization of Tramadol or M1 was > 15 times slower than O-methylation, and was only observed in the presence of added CH₃I carrier.