STUDIES WITH DIFFERENTIALLY LABELED [C-11] COCAINE [C-11] NORCOCAINE,[C-11] BENZOYLECGONINE, AND [C-11] AND 4'-[F-18]FLUOROCOCAINE TO PROBE THE EXTENT TO WHICH [C-11] COCAINE METABOLITES CONTRIBUTE TO PET IMAGES OF THE BABOON BRAIN

The psychostimulant drug of abuse, cocaine (benzoylecgonine methyl est er), is rapidly metabolized by cleavage of its two ester groups, to gi ve benzoylecgonine (BE) and ecgonine methyl ester, and by N-demethylat ion, to give N-norcocaine (NC). The recent use of [N-methyl-(CH3)-C-11 ]cocaine to image brain cocaine binding sites with positron emission t omography (PET) raises the question of whether PET images partially re flect the distribution and kinetics of labeled cocaine metabolites. We prepared [O-methyl-(CH3)-C-11]cocaine by methylation of the sodium sa lt of BE with [C-11]CH(3)l, and showed that PET baboon brain scans, as well as regional brain kinetics and plasma time-activity curves corre cted for the presence of labeled metabolites, are nearly identical to those seen with [N-methyl-(CH3)-C-11]cocaine. This strongly suggests t hat C-11 metabolites do not significantly affect PET images, because t he metabolite pattern is different for the two labeled forms of cocain e. In particular, nearly half the C-11 in blood plasma at 30 min was [ C-11]CO2 when [N-methyl-(CH3)-C-11]cocaine was administered, whereas [ C-11]CO2 was not formed from [O-methyl-(CH3)-C-11]cocaine. Only a trac e of [C-11]NC was detected in plasma after [O-methyl-(CH3)-C-11]cocain e administration. Nearly identical brain PET data were also obtained w hen 4'-[N-methyl-(CH3)-C-11]fluorococaine and 4'-[F-18]fluorococaine ( prepared by nucleophilic aromatic substitution from [F-18]fluoride- an d 4'-nitrococaine) were compared with [N-methyl-(CH3)-C-11]cocaine. In vitro assays with rat brain membranes showed that cocaine and 4'-fluo rococaine were equipotent at the dopamine reuptake site, but that 4'-f luorococaine was about 100 times more potent at the 5-hydroxytryptamin e reuptake site. The studies with positron-emitting 4'-fluorococaines thus support the lack of significance of labeled metabolites or of bin ding to 5-hydroxytryptamine reuptake sites to PET images taken with [N -methyl-(CH3)-C-11]cocaine. [C-11]NC prepared by O-methylation of norb enzoylecgonine gave PET images with preferential uptake in striatum, b ut slower clearance from all brain regions than [O-methyl-(CH3)-C-11]c ocaine. [C-11]BE prepared by N-methylation of norbenzoylecgonine did n ot show brain uptake.