Cerebral 6-[(18)F]fluoro-L-DOPA (FDOPA) metabolism in pig studied by positron emission tomography.
We measured 6-[(18)F]fluoro-L-DOPA (FDOPA) uptake and metabolism in the brain of 4-month-old female pigs (n = 8) using a high-resolution positron emission tomograph (PET) in 3D mode. The mean net blood-brain clearance of FDOPA (K(i)(D)) to striatum was 0.011 ml g(-1) min(-1). Correcting for the elimination of decarboxylated metabolites from striatum (k(loss) = 0.004 min(-1)) increased the apparent magnitude of the estimate of K(i)(D) by 50%, at the expense of doubling the variance of the mean estimate. The mean decarboxylation rate of FDOPA in striatum relative to the cerebellum input (k(3)(s)) was 0.008 min(-1). For multicompartmental analyses, the FDOPA partition volume (V(e)(D)) was constrained to the individual value observed in cerebellum (mean = 0.53 ml g(-1)), with correction for the presence in brain of the plasma metabolite 3-O-methyl-FDOPA (OMFD). Using the first 60 min of the dynamic PET scans, the rate constant of FDOPA decarboxylation (k(3)(D)) was estimated to be 0.037 min(-1 )in striatum, but was not significantly different than zero in frontal cortex. Fitting of a compartmental model correcting for elimination of decarboxylated metabolites to the complete PET frame-sequence (120 min) increased the variance of the estimate of k(3)(D) in striatum. The magnitude of k(3)(D) in striatum of young pig was less than values estimated previously in neonatal piglet, adult monkey, and human. MRI-based simulations predicted that recovery of radioactivity from pig striatum was highly sensitive to the volume of interest. We conclude that the spatial resolution of our tomograph reduces the apparent magnitude of k(3)(D) in striatum. However, anaesthetised pigs are an appropriate experimental model for PET studies of DOPA decarboxylation in striatum.
Danielsen
E H
EH
PET-Center, Aarhus University Hospital, DK-8000 Aarhus C, Denmark. erik@pet.auh.dk
Smith
D F
DF
Gee
A D
AD
Venkatachalam
T K
TK
Hansen
S B
SB
Hermansen
F
F
Gjedde
A
A
Cumming
P
P
D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002230:Carbidopa / Q000494:pharmacology; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005462:Fluorine Radioisotopes / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007700:Kinetics; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D008959:Models, Neurological; D051381:Rats; D013552:Swine; D014055:Tomography, Emission-Computed
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D005462:Fluorine Radioisotopes; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; D002230:Carbidopa