Effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin and infusion of L-tyrosine on the in vivo L-[beta-11C] DOPA disposition in the monkey brain.
The effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) and L-tyrosine infusion on [11C]dopamine synthesis was analyzed in the striatum of Rhesus using positron emission tomography (PET). The rate for decarboxylation from L-[beta-11C]DOPA to [11C]dopamine was calculated using a graphical method with cerebellum as a reference region. Although the peripheral administration of 6R-BH4 at low dose (2 mg/kg) did not provide a significant increase in the rate of dopamine biosynthesis, a high dose of 6R-BH4 (20 mg/kg) induced an elevation of the rate. This 6R-BH4-induced elevation of the dopamine synthesis rate was further dose-dependently enhanced by the continuous infusion of L-tyrosine (0.2 and 1.0 mumol/min/kg). L-Tyrosine infusion with a rate of 1.0 mumol/min/kg caused an enhancement of the rate even during low dose administration of 6R-BH4 (2 mg/kg). L-Tyrosine infusion alone did not induce any elevation of the dopamine biosynthesis rate. The analysis of plasma indicated that the metabolic ratios of L-[beta-11C]DOPA to each metabolite were not affected by 6R-BH4 and/or L-tyrosine infusion. The results suggest that the low dose loading of tyrosine facilitates the activity of 6R-BH4 on the presynaptic dopamine biosynthesis, and also that the combined effects can be monitored by PET using L-[beta-11C]DOPA as a biochemical probe.
Tsukada
H
H
Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan.
Lindner
K J
KJ
Hartvig
P
P
Tani
Y
Y
Valtysson
J
J
Bjurling
P
P
Kihlberg
T
T
Westerberg
G
G
Watanabe
Y
Y
Långström
B
B
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects*; D004295:Dihydroxyphenylalanine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008253:Macaca mulatta; D013997:Time Factors; D014443:Tyrosine / Q000494:pharmacology*
D000975:Antioxidants; D001708:Biopterins; D014443:Tyrosine; D004295:Dihydroxyphenylalanine; C003402:sapropterin