Different brain radioactivity curves in a PET study with [11C]beta-CIT labelled in two different positions

The cocaine congener 2beta-carbomethoxy-3beta-(4'-iodophenyl)tropane (beta-CIT) has a chemical structure that enables labelling with carbon-11 either by N-methylation or by O-methylation. The regional brain uptake of [N-methyl-11C]beta-CIT and [O-methyl-11C]beta-CIT was compared in cynomolgus monkeys using positron emission tomography (PET). The striatal uptake of radioactivity after intravenous injection of [O-methyl-11C]beta-CIT reached a plateau at 30-40 min, whereas the uptake of [N-methyl-11C]beta-CIT increased continuously during the time of the PET measurement. Two of the putative labelled metabolites, [N-methyl-11C]beta-CIT-acid and [O-methyl-11C]nor-beta-CIT were prepared and examined with PET to investigate if they may enter the brain and thus add to the radioactivity uptake obtained with [11C]beta-CIT. Less than 0.4% of injected [N-methyl-11C]beta-CIT-acid entered the brain whereas 5-6% of [O-methyl-11C]nor-beta-CIT entered the brain and accumulated in the striatum and in the thalamus. The fraction of [O-methyl-11C]nor-beta-CIT obtained in plasma after intravenous injection of [O-methyl-11C]nor-beta-CIT, however, never exceeded 3%. Consequently, the formation of [N-methyl-11C]beta-CIT-acid and [O-methyl-11C]nor-beta-CIT cannot be the explanation for the different time-activity curves in the monkey brain demonstrated with [11C]beta-CIT labelled in two different positions. An unidentified labelled lipophilic metabolite, detected in monkey plasma after injection of [O-methyl-11C]beta-CIT, remains as the only possible explanation for the differences between [N-methyl-11C]beta-CIT and [O-methyl-11C]beta-CIT.