Comparative in vivo metabolism of 6-[18F]fluoro-L-dopa and [3H]L-dopa in rats.
In vivo double-label experiments in rats were designed to correlate the peripheral and cerebral metabolism of 6-[18F]fluoro-L-DOPA [( 18F]FDOPA) with that of [3H]L-DOPA. Authentic samples of the major [18F]FDOPA metabolites were synthesized to identify the 18F-labeled metabolites. After carbidopa pretreatment and intravenous administration of the compound, the products of peripheral metabolism in plasma were analyzed at times from 3 to 60 min. In the periphery, amine conjugates were detected but they accounted for less than 15% of the total radioactivity; the major metabolites were 3-O-methyl-6-[18F]fluoro-L-DOPA and 3-O-methyl-[3H]L-DOPA. The rate and extent of 3-O-methylation of [18F]FDOPA exceeded that of [3H]L-DOPA. Both 3-O-methylated products entered the striatum and cerebellum where they contributed significant but uniform activity. Analysis of cerebral metabolism in these structures indicated a linear accumulation of total radioactivity: a striatum/cerebellum ratio of 2 was observed by 60 min. 6-[18F]Fluorodopamine (35%) and [3H]dopamine (55%) were the major metabolites formed in the striatum: however, the methylated [18F]FDOPA and [3H]DOPA products of predominantly peripheral origin represented 55% (18F) and 35% (3H) of the total radioactivity respectively. Other [3H]dopamine metabolites and their 18F-labeled analogs represented less than 10-15% at all times analyzed. The cerebellum radioactivity was composed only of [18F]FDOPA, [3H]DOPA and their 3-O-methylated products. These data will serve as the basis for the development of kinetic models of [18F]FDOPA metabolism that can be applied to the evaluation of central dopamine biochemistry with positron emission tomography in humans.
Melega
W P
WP
Department of Radiological Sciences, UCLA School of Medicine 90024.
Luxen
A
A
Perlmutter
M M
MM
Nissenson
C H
CH
Phelps
M E
ME
Barrio
J R
JR
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002230:Carbidopa / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D005462:Fluorine Radioisotopes; D007275:Injections, Intravenous; D007700:Kinetics; D007980:Levodopa / Q000097:blood / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014316:Tritium
D005462:Fluorine Radioisotopes; D014316:Tritium; C043437:fluorodopa F 18; D007980:Levodopa; D004295:Dihydroxyphenylalanine; D002230:Carbidopa