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Studies with Differentially Labeled [ 11 C]Cocaine, [ 11 C]Norcocaine, [ 11 C]Benzoylecgonine, and [ 11 C]‐and 4′‐[ 18 F]Fluorococaine to Probe the Extent to Which [ 11 C]Cocaine Metabolites Contribute to PET Images of the Baboon Brain
Author(s) -
Gatley S. John,
Yu DingWei,
Fowler Joanna S.,
MacGregor Robert R.,
Schlyer David J.,
Dewey Stephen L.,
Wolf Alfred P.,
Martin Thomas,
Shea Colleen E.,
Volkow Nora D.
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.62031154.x
Subject(s) - benzoylecgonine , chemistry , metabolite , stereochemistry , biochemistry
The psychostimulant drug of abuse, cocaine (benzoylecgonine methyl ester), is rapidly metabolized by cleavage of its two ester groups, to give benzoylecgonine (BE) and ecgonine methyl ester, and by N ‐demethylation, to give N ‐norcocaine (NC). The recent use of [ N‐methyl ‐ 11 CH 3 ]cocaine to image brain cocaine binding sites with positron emission tomography (PET) raises the question of whether PET images partially reflect the distribution and kinetics of labeled cocaine metabolites. We prepared [ O ‐ metty /‐ 11 CH 3 ]cocaine by methylation of the sodium salt of BE with [ 11 C]CH 3 l, and showed that PET baboon brain scans, as well as regional brain kinetics and plasma time‐activity curves corrected for the presence of labeled metabolites, are nearly identical to those seen with [ N‐methyl ‐ 11 CH 3 ]cocaine. This strongly suggests that 11 C metabolites do not significantly affect PET images, because the metabolite pattern is different for the two labeled forms of cocaine. In particular, nearly half the 11 C in blood plasma at 30 min was [ 11 C]CO 2 when [ N ‐ methy /‐ 11 CH 3 ]cocaine was administered, whereas [ 11 C]CO 2 was not formed from [O‐ methy /‐ 11 CH 3 ]cocaine. Only a trace of [ 11 C]NC was detected in plasma after [ O ‐methyl‐ 11 CH 3 ]cocaine administration. Nearly identical brain PET data were also obtained when 4′‐[ N ‐ methy /‐ 11 CH 3 ]fluorococaine and 4′‐[ 18 F]fluoro‐cocaine (prepared by nucleophilic aromatic substitution from [ 18 F]fluoride‐and 4′‐nitrococaine) were compared with [ N ‐methy/‐ 11 CH 3 ]cocaine. In vitro assays with rat brain membranes showed that cocaine and 4′‐fluoroco‐caine were equipotent at the dopamine reuptake site, but that 4′‐fluorococaine was about 100 times more potent at the 5‐hydroxytryptamine reuptake site. The studies with positron‐emitting 4′‐fluorococaines thus support the lack of significance of labeled metabolites or of binding to 5‐hydroxytryptamine reuptake sites to PET images taken with [ N ‐ methy /‐ 11 CH 3 ]cocaine. [ 11 C]NC prepared by O ‐methylation of norbenzoylecgonine gave PET images with preferential uptake in striatum, but slower clearance from all brain regions than [O‐ methy /‐ 11 CH 3 ]cocaine. [ 11 C]BE prepared by N ‐methylation of norbenzoylecgonine did not show brain uptake.