Altered metabolism of [18F]-6-fluorodopa in the hooded rat following inhibition of catechol-O-methyltransferase with U-0521.
[18F]-6-Fluoro-L-DOPA ([18F]DOPA), a tracer for cerebral dopamine in studies utilizing positron emission tomography (PET), is rapidly metabolized by catechol-O-methyltransferase (COMT) in the periphery following intravenous injection to carbidopa-pretreated humans and rats. Experiments were performed to determine the effect of pretreatment with 3',4'-dihydroxy-2-methyl-propiophenone (U-0521), a competitive inhibitor of COMT, on [18F]DOPA metabolism in the carbidopa-pretreated hooded rat. U-0521 (25 mg/kg, i.p.), administered 10 min prior to the [18F]DOPA, served to increase the persistence of [18F]DOPA in plasma over a 2-hr period by decreasing the rate of formation of the peripheral metabolite 3-O-methyl-6-fluorotyrosine (Me[18F]DOPA). This compound passes readily into brain and was the sole [18F]DOPA metabolite observed in cortex and cerebellum. U-0521 produced a short-lasting decrease in Me[18F]DOPA levels in these two tissues. In striatum, decreases in Me[18F]DOPA were found to last at least 90 min. Associated with the elevated availability of [18F]DOPA in plasma produced by U-0521 were 50% increases in striatal [18F]dopamine ([18F]DA) levels and 40% increases in the levels of [18F]dihydroxyphenylacetic acid ([18F]DOPAC) at times between 30 and 90 min following [18F]DOPA injection. Increased decarboxylation of [18F]DOPA in the striatum of U-0521-treated rats resulted in heightened radiocontrast between striatum and other cerebral tissues.
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D065098:Catechol O-Methyltransferase Inhibitors; D003342:Corpus Striatum / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D007700:Kinetics; D011427:Propiophenones / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D065098:Catechol O-Methyltransferase Inhibitors; D011427:Propiophenones; D015102:3,4-Dihydroxyphenylacetic Acid; C043437:fluorodopa F 18; C006104:U 0521; D004295:Dihydroxyphenylalanine; D004298:Dopamine