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

Gabriel Léger, Albert Gjedde, Hiroto Kuwabara, Mark Guttman, Paul Cumming

Research output: Contribution to journalArticle

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-[18F]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 [18F]fluorodopamine synthesis in striatum was potentiated. However, OR-611 treatment reduced the unidirectional (K1/(D)) and net (K(i)) blood-brain clearances of FDOPA, and also inhibited the rate of decarboxylation (k3/(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 k3/(D) were insensitive to the magnitude of the permeability ratio. In the control group, the estimate of k3/(D) increased by 40% as the magnitude of the constrained permeability ratio increased in the range of published estimates.

Original languageEnglish (US)
Pages (from-to)351-361
Number of pages11
JournalSynapse
Volume30
Issue number4
DOIs
StatePublished - Dec 1 1998

Keywords

  • Catechol-O-methyltransferase
  • Compartmental models
  • Dopa decarboxylase
  • Fluorodopa
  • Inhibitors
  • Kinet- ics

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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