Striatal 6-[18F]fluorodopa accumulation after combined inhibition of peripheral catechol-O-methyltransferase and monoamine oxidase type B: differing response in relation to presynaptic dopaminergic dysfunction.
The aim was to investigate the effects of inhibition of monoamine oxidase type B (MAO-B) with selegiline alone and the combined inhibition of peripheral catechol-O-methyltransferase (COMT) with entacapone and MAO-B with selegiline on striatal 6-[18F]fluorodopa (FDOPA) accumulation, and whether the effect of entacapone + selegiline on FDOPA uptake differed depending on the severity of the presynaptic dopaminergic dysfunction. Thus, eight healthy controls, eight de novo patients with Parkinson's disease (PD), and 18 levodopa-treated PD patients were investigated with positron emission tomography (PET). Half of the subjects in each population belonged to the selegiline group and half to the entacapone + selegiline group. Both groups were studied twice with PET using FDOPA. After the first (baseline) FDOPA PET investigation, both groups were on 2 weeks of selegiline treatment, 10 mg daily. Thereafter, the second FDOPA PET was performed for all subjects with a premedication administered 60 min before the PET imaging; one group received 10 mg of selegiline, and the other group received a single 400 mg dose of entacapone coadministered with 10 mg of selegiline. Selegiline treatment alone had no significant influence on striatal FDOPA metabolism. The FDOPA accumulation, expressed as striatal-to-occipital ratios and modified decarboxylation coefficients (k3R0), increased significantly after entacapone + selegiline administration in all subject populations. The FDOPA uptake rate constant (Ki) remained virtually unchanged in controls and in de novo patients but decreased significantly in levodopa-treated PD patients after entacapone + selegiline intake. Entacapone + selegiline administration did not influence significantly the unidirectional blood-to-brain clearance for FDOPA (K1D) or the relative dopadecarboxylase activity (k3D). The changes in the studied parameters after entacapone + selegiline administration probably reflect the effects of entacapone, since entacapone alone has caused similar changes in previous PET studies. Response in FDOPA accumulation to entacapone + selegiline was higher in controls and de novo patients compared with levodopa-treated PD patients. The milder response in levodopa-treated patients might reflect the reduced ability of the degenerated dopaminergic neurons to utilize the prolonged FDOPA availability, produced by entacapone.
Ruottinen
H M
HM
Department of Neurology, University of Turku, Finland. hanna.ruottinen@utu.fi
Rinne
J O
JO
Oikonen
V J
VJ
Bergman
J R
JR
Haaparanta
M T
MT
Solin
O H
OH
Ruotsalainen
U H
UH
Rinne
U K
UK
D000328:Adult; D000368:Aged; D000978:Antiparkinson Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D065098:Catechol O-Methyltransferase Inhibitors; D003342:Corpus Striatum / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism; D004298:Dopamine / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000494:pharmacology*; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use; D017729:Presynaptic Terminals / Q000187:drug effects; D011869:Radioligand Assay; D012642:Selegiline / Q000627:therapeutic use; D014055:Tomography, Emission-Computed
D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D005462:Fluorine Radioisotopes; D008996:Monoamine Oxidase Inhibitors; C043437:fluorodopa F 18; D012642:Selegiline; D004295:Dihydroxyphenylalanine; D008995:Monoamine Oxidase; D004298:Dopamine