title: Central action of benserazide after COMT inhibition demonstrated in vivo by PET.
abstract: Positron emission tomography (PET) following intravenous administration of beta-[11C]-L-DOPA provides a method of assessing regional cerebral uptake and utilization of levodopa. Cerebral levodopa kinetics in the rhesus monkey were investigated after the inhibition of catechol-O-methyltransferase (COMT) with RO 40-7592, and after coadministration of the peripheral aromatic L-amino acid decarboxylase (AADC) inhibitors benserazide and carbidopa. Pretreatment with RO 40-7592 (10 mg/kg), benserazide (10 mg/kg) or carbidopa (3.5 mg/kg) did not change striatal k3, which mainly reflects the ability for the brain tissue to convert [11C]-L-DOPA to [11 C]-dopamine, although the brain's uptake of radioactivity increased substantially after pretreatment with the AADC inhibitors. When benserazide was coadministered with RO 40-7592 (10 mg/kg) a dose-dependent decrease in striatal k3 was measured with an apparent ED50 of 3 mg/kg. No such effect was indicated after pretreatment with the combination of RO 40-7592 (10 mg/kg) and carbidopa (3.5 mg/kg). The possible negative interactions of coadministration with COMT inhibitors and predominantly peripherally acting AADC inhibitors must be considered when used in the therapy of Parkinson's disease.
authors.affiliation: Department of Neurology, University Hospital, Uppsala University, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Tedroff
authors.forename: P
authors.initials: P
authors.lastname: Hartvig
authors.forename: P
authors.initials: P
authors.lastname: Bjurling
authors.forename: Y
authors.initials: Y
authors.lastname: Andersson
authors.forename: G
authors.initials: G
authors.lastname: Antoni
authors.forename: B
authors.initials: B
authors.lastname: Långström
mesh_terms: D000818:Animals; D001545:Benserazide / Q000494:pharmacology*; D001577:Benzophenones / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors; D007980:Levodopa / Q000378:metabolism*; D008253:Macaca mulatta; D009596:Nitrophenols; D010300:Parkinson Disease / Q000378:metabolism; D000077867:Tolcapone; D014055:Tomography, Emission-Computed
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D009596:Nitrophenols; D007980:Levodopa; D001545:Benserazide; D000077867:Tolcapone