Administration of the new COMT inhibitor OR-611 increases striatal uptake of fluorodopa.
L-Dopa is metabolized to 3-O-methyldopa (3OMD) by catechol-O-methyltransferase (COMT). This reduces the amount of L-dopa available for entry into brain. We studied the effect of OR-611, a new COMT inhibitor, on plasma and brain 6-[18F]-fluoro-L-dopa (6FD) metabolism in cynomolgus monkeys with positron emission tomography (PET). OR-611 pretreatment substantially reduced plasma 6FD metabolism to 3-O-methylfluorodopa (3OMFD). PET measurements of striatal 6FD concentrations showed an average 2.3-fold increase following OR-611 pretreatment, compared to the same animals in the control state. OR-611 inhibits plasma metabolism of 6FD and increases brain uptake of this L-dopa analog. OR-611 appears to be a promising agent as an adjunct to L-dopa for the treatment of patients with Parkinson's disease.
Guttman
M
M
McConnell Brain Imaging Centre, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Léger
G
G
Reches
A
A
Evans
A
A
Kuwabara
H
H
Cedarbaum
J M
JM
Gjedde
A
A
D000818:Animals; D002396:Catechols / Q000493:pharmacokinetics / Q000494:pharmacology*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism*; D008252:Macaca fascicularis; D008279:Magnetic Resonance Imaging; D008297:Male; D009570:Nitriles; D010300:Parkinson Disease / Q000188:drug therapy; D014055:Tomography, Emission-Computed
D002396:Catechols; D005462:Fluorine Radioisotopes; D009570:Nitriles; C043437:fluorodopa F 18; D007980:Levodopa; C071192:entacapone; D004295:Dihydroxyphenylalanine