Effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on in vivo L-[beta-11C]dopa turnover in the rat striatum with infusion of L-tyrosine.
L-[11C]DOPA, combined with positron emission tomography (PET), has made possible the assessment of dopamine turnover in vivo. Before the evaluation of PET study with L-[11C]DOPA in the primate, the effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) and/or L-tyrosine infusion on L-[11C]DOPA turnover was analyzed in the rat striatal tissue and in the striatal extracellular fluid using microdialysis. L-[11C]DOPA was rapidly taken up into the brain after intravenous injection and converted to [11C]dopamine, [11C]DOPAC and [11C]HVA in the striatal tissue. Small amount of 3-O-methyl-[11C]DOPA, a product of DOPA by 3-O-methylation in peripheral tissues, was also detected in the striatal tissue. The striatum/cerebellum ratio of total radioactivity uptake was linear against time up to 40 min after L-[11C]DOPA injection. The uptake ratio, increased by 6R-BH4 administration, was further increased by L-tyrosine infusion. The in vivo microdialysis technique was further applied to determine L-[11C]DOPA and its metabolites in striatal extracellular fluid (ECF). The peripheral administration of 6R-BH4 (50 mg/kg) induced elevation of [11C]DOPA concentration in ECF in the early phase after injection, following higher radioactivity in [11C]dopamine and [11C]HVA fractions than those in control animals at late phase. The 6R-BH4-induced elevation of [11C]DOPA uptake and the radioactivity of its metabolites was further enhanced by the continuous infusion of L-tyrosine at a dose of 1.0 mumol/min/kg. L-Tyrosine infusion alone did not induce the elevation of radioactivity. The results suggest that [11C]DOPA might be a useful probe to evaluate the effect of 6R-BH4 and/or L-tyrosine loading in the primate.
Central Research Laboratory PET Center, Hamamatsu Photonics K. K., Shizuoka, Japan.
H
H
Tsukada
K J
KJ
Lindner
P
P
Hartvig
Y
Y
Tani
P
P
Bjurling
T
T
Kihlberg
G
G
Westerberg
Y
Y
Watanabe
B
B
Långström
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D002250:Carbon Radioisotopes; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000378:metabolism* / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D014055:Tomography, Emission-Computed; D014443:Tyrosine / Q000494:pharmacology*
D002250:Carbon Radioisotopes; D001708:Biopterins; D014443:Tyrosine; D004295:Dihydroxyphenylalanine; C003402:sapropterin; D004298:Dopamine; D006719:Homovanillic Acid