Premium
Effect of catechol‐ O ‐methyltransferase inhibition on brain uptake of [ 18 F]fluorodopa: Implications for compartmental modelling and clinical usefulness
Author(s) -
Léger Gabriel,
Gjedde Albert,
Kuwabara Hiroto,
Guttman Mark,
Cumming Paul
Publication year - 1998
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/(sici)1098-2396(199812)30:4<351::aid-syn2>3.0.co;2-2
Subject(s) - catechol o methyl transferase , chemistry , neuroscience , methyltransferase , pharmacology , catechol , psychology , biochemistry , medicine , allele , gene , methylation
Abstract The efficacy of levo‐DOPA in the treatment of Parkinson's disease is potentiated by blockade of its peripheral metabolism with inhibitors of catechol‐ O ‐methyltransferase (COMT). Some COMT inhibitors may act entirely in the periphery (nitecapone, OR‐462), while others may also have some activity in brain (entacapone, OR‐611). We used positron emission tomography (PET) to test the effects of these two COMT inhibitors on the plasma kinetics and brain metabolism of the levo‐DOPA analog 6‐[ 18 F]fluoro‐L‐dopa (FDOPA) in cynomolgus monkeys, employing a compartmental model for the assay of DOPA decarboxylase activity in living brain. Four monkeys each underwent two PET scans in the baseline condition, 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 circulation, and increased the ratio of the radioactivity concentrations in striatum and occipital cortex, suggesting that [ 18 F]fluorodopamine synthesis 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 partially 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 groups with COMT inhibition, the estimates of k 3 Dwere insensitive to the magnitude of the permeability ratio. In the control group, the estimate of k 3 Dincreased by 40% as the magnitude of the constrained permeability ratio increased in the range of published estimates. Synapse 30:351–361, 1998. © 1998 Wiley‐Liss, Inc.