CEREBRAL 6-[F-18]FLUORO-L-DOPA UPTAKE IN RHESUS-MONKEY - PHARMACOLOGICAL INFLUENCE OF AROMATIC AMINO-ACID DECARBOXYLASE (AAAD) AND CATECHOL-O-METHYLTRANSFERASE (COMT) INHIBITION

FDOPA/PET scans were performed in one rhesus monkey to study the influ ence of three catechol-O-methyltransferase (COMT) inhibitors (CGP 2801 4, OR-611 and Ro 40-7592) on FDOPA pharmacokinetics. COMT inhibitors w ere administered in combination with carbidopa, a peripherally acting inhibitor of the aromatic amino acid decarboxylase (AAAD). FDOPA was a dministered intravenously and its metabolic fate in plasma was determi ned using an HPLC system with an on-line gamma-gamma coincidence detec tor. Cerebral tracer uptake was assessed in the striatum and in a non- dopaminergic brain region (occipital cortex). In the periphery, the ph armacokinetic efficiency of FDOPA was increased due to the combined in hibition of COMT and AAAD activity. All three COMT inhibitors reduced the FDOPA methylation rate constant in plasma, with complete suppressi on obtained in the case of Ro 40-7592. In the brain, specific F-18 rad ioactivity (striatal minus brain reference radioactivity) increased as a result of the increase in FDOPA plasma availability following the a dministration of COMT and AAAD inhibitors. We established a significan t linear correlation between striatal radioactivity and FDOPA plasma l evels (r = 0.924 +/- 0.048, P < 0.0001 for total striatal and r = 0.94 8 +/- 0.054, P < 0.0001 for specific striatal radioactivity). Using pl asma FDOPA radioactivity as input, we found that the striatal FDOPA up take rate constant K-i(FD) was not changed by any of the inhibitors. T hus, the enhancement of striatal radioactivity after application of en zyme inhibitors is a consequence of the increase in plasma FDOPA that becomes available for conversion to fluorodopamine in the striatal dop aminergic nerve terminals. By contrast, using the radioactivity in a n on-dopaminergic region (cortex) as input, we found that the striatal F DOPA uptake rate constant K-i(ref) was significantly (P < 0.0001) incr eased following pretreatment with COMT inhibitors. Our analysis demons trated that K-i(ref) and the 3-OMFD contribution to the cerebral radio activity were inversely correlated. (C) 1997 Elsevier Science B.V.