Fluorodopa positron emission tomography with an inhibitor of catechol-O-methyltransferase: effect of the plasma 3-O-methyldopa fraction on data analysis.
Flurodopa (FDOPA) is an analogue of L-di-hydroxyphenylalanine (L-dopa) used to assess the nigrostriatal dopamine system in vivo with positron emission tomography (PET). However, FDOPA/PET quantitation is complicated by the presence of the 3-O-methyl-FDOPA (3OMFD) fraction in brain and plasma. Pretreatment with entacapone (OR-611), a peripheral catechol O-methyl-transferase (COMT) inhibitor, greatly reduces the plasma 3OMFD fraction and provides an ideal situation to evaluate the contribution of the plasma 3OMFD fraction in several kinetic models of FDOPA uptake. We performed FDOPA/PET with and without the OR-611 preadministration in six Parkinson's disease (PD) patients. We measured the time-course of the plasma FDOPA and 3OMFD fractions using high-pressure liquid chromatography (HPLC). We calculated striato-occipital ratios (SOR), and estimated the striatal FDOPA uptake rate constant graphically using the plasma FDOPA and occipital tissue time activity curves (KiFD and KiOCC, respectively). We also estimated striatal dopa decarboxylase (DDC) activity (k3D) using a model incorporating independent measurements of 3OMFD transport kinetic rate constants. With the preadministration of OR-611, the pharmacological efficiency in plasma was prolonged significantly (21.1-37.7%; p < 0.01). We also observed significant mean elevations in SOR and KiOCC by 21.8 and 53.5%, respectively (p < 0.05). KiFD and k3D did not show significant change. We conclude that OR-611 prolongs the circulation time of FDOPA in the plasma but does not alter rate constants for striatal FDOPA uptake or decarboxylation.
Ishikawa
T
T
Department of Neurology, North Shore University Hospital/Cornell, University Medical College, Manhasset, New York 11030, USA.
Dhawan
V
V
Chaly
T
T
Robeson
W
W
Belakhlef
A
A
Mandel
F
F
Dahl
R
R
Margouleff
C
C
Eidelberg
D
D
D000328:Adult; D000368:Aged; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D009778:Occipital Lobe / Q000378:metabolism; D010300:Parkinson Disease / Q000097:blood*; D011786:Quality Control; D012680:Sensitivity and Specificity; D014055:Tomography, Emission-Computed / Q000379:methods* / Q000706:statistics & numerical data; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000097:blood
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D005462:Fluorine Radioisotopes; D009570:Nitriles; C043437:fluorodopa F 18; D014443:Tyrosine; C071192:entacapone; D004295:Dihydroxyphenylalanine; C008404:3-methoxytyrosine