EFFECT OF CATECHOL-O-METHYLTRANSFERASE INHIBITION ON BRAIN UPTAKE OF [F-18] FLUORODOPA - IMPLICATIONS FOR COMPARTMENTAL MODELING AND CLINICAL USEFULNESS

The efficacy of levo-DOPA in the treatment of Parkinson's disease is p otentiated by blockade of its peripheral metabolism with inhibitors of catechol-O-methyltransferase (COMT). Some COMT inhibitors may act ent irely in the periphery (nitecapone, OR-462), while others may also hav e some activity in brain (entacapone, OR-611). We used positron emissi on tomography (PET) to test the effects of these two COMT inhibitors o n the plasma kinetics and brain metabolism of the levo-DOPA analog 6-[ F-18]fluoro-L-dopa (FDOPA) in cynomolgus monkeys, employing a compartm ental model for the assay of DOPA decarboxylase activity in living bra in. Four monkeys each underwent two PET scans in the baseline conditio n, one PET scan after treatment with OR-462 (15 mg/kg, i.v.), and one PET scan after treatment with OR-611 (15 mg/kg, i.v.). Pharmacokinetic analysis of FDOPA metabolism in plasma indicated that these compounds blocked peripheral COMT activity by 80% for at least 60 minutes. Both COMT inhibitors increased the net availability of FDOPA in circulatio n, and increased the ratio of the radioactivity concentrations in stri atum and occipital cortex, suggesting that [F-18]fluorodopamine synthe sis in striatum was potentiated. However, OR-611 treatment reduced the unidirectional (K-1(D)) and net (K-i) blood-brain clearances of FDOPA , and also inhibited the rate of decarboxylation (k(3)(D)) of FDOPA in striatum. These observations suggest that high doses of OR-611 may pa rtially antagonize the cerebral utilization of levo-DOPA. We used the present data to test the sensitivity of the compartmental model to the physiological constraint that the blood-brain permeabilities of the O -methylated plasma metabolite and FDOPA have a fixed ratio. In the gro ups with COMT inhibition, the estimates of k(3)(D) were insensitive to the magnitude of the permeability ratio. In the control group, the es timate of k(3)(D) increased by 40% as the magnitude of the constrained permeability ratio increased in the range of published estimates. (C) 1998 Wiley-Liss, Inc.