Effect of catechol-O-methyltransferase inhibition on brain uptake of [18F]fluorodopa: implications for compartmental modelling and clinical usefulness.

摘要: The efficacy of levo-DOPA in the treatment Parkinson's disease is potentiated by blockade its peripheral metabolism with inhibitors catechol-O-methyltransferase (COMT). Some COMT may act entirely periphery (nitecapone, OR-462), while others also have some activity brain (entacapone, OR-611). We used positron emission tomography (PET) to test effects these two on plasma kinetics and analog 6-[18F]fluoro-L-dopa (FDOPA) cynomolgus monkeys, employing a compartmental model for assay DOPA decarboxylase living brain. Four monkeys each underwent PET scans baseline condition, one scan after OR-462 (15 mg/kg, i.v.), OR-611 i.v.). Pharmacokinetic analysis FDOPA indicated that compounds blocked 80% at least 60 minutes. Both increased net availability circulation, ratio radioactivity concentrations striatum occipital cortex, suggesting [18F]fluorodopamine synthesis was potentiated. However, reduced unidirectional (K1D) (Ki) blood-brain clearances FDOPA, inhibited rate decarboxylation (k3D) striatum. These observations suggest high doses partially antagonize cerebral utilization levo-DOPA. present data sensitivity physiological constraint permeabilities O-methylated metabolite fixed ratio. In groups inhibition, estimates k3D were insensitive magnitude permeability control group, estimate 40% as constrained range published estimates.