Altered metabolism of [ 18F]-6-fluorodopa in the hooded rat following inhibition of catechol-O-methyltransferase with U-0521

Abstract

[ 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.