COMT INHIBITORS AND METABOLISM OF FLUORODOPA ENANTIOMERS IN AGGREGATING CELL-CULTURES

Organotypic primary cell cultures of fetal rat brain were used as a mo del system to study the effect of COMT inhibitors on the cerebral meta bolic conversions of fluoro-DOPA enantiomers. The selective COMT inhib itors OR 486 and CGP 28014 were used in conjunction with 5F-L-DOPA, 6F -L-DOPA and 6F-D-DOPA as substrates. Methylation can be clearly reduce d by application of OR 486 at nanomolar level, without inhibition of A ADC and MAO. The uptake of the substrate is un changed. CGP 28014, alr eady known to be active only in vivo, has no influence on the metaboli c conversion rates of the fluoro-DOPA isomers. These results show that use of this culture system allows statement concerning the in vitro a ctivity of COMT inhibitors. It has not been possible to show an increa se of absolute levels of decarboxylation products due to inhibition of COMT, however, but the reduction in levels of methylated product itse lf may have significance for PET studies of the human brain.