6-[18F]fluoro-L-dopa uptake and [76Br]bromolisuride binding in the excitotoxically lesioned caudate-putamen of nonhuman primates studied using positron emission tomography.
The functional status of the dopaminergic system following striatal excitotoxic lesions was studied in living baboons by positron emission tomography (PET) using 6-[18F]fluoro-L-dopa as specific tracer for the presynaptic dopaminergic terminals and [76Br]bromolisuride as selective dopamine D2-receptor marker. The glutamate receptor agonist ibotenic acid (IA) was injected into the right caudate-putamen of six baboons to induce a neuropathological and behavioral model of Huntington's disease (HD). In vivo PET studies performed 3 to 6 months after the IA injections showed that subtotal excitotoxic lesions of the CP were accompanied by changes in the kinetic of [76Br]bromolisuride binding indicating a dose-dependent reduction in binding sites in the lesioned striatum of all IA-injected animals. In the most severely lesioned animals, there was also a decrease in the uptake of the nigrostriatal dopaminergic marker. The loss of D2-receptors and decrease in striatal dopamine uptake are consistent with clinical and postmortem findings in HD. In addition, the decrease in 6-[18F]fluoro-L-dopa uptake confirms previous studies performed in a rat model of HD suggesting a continuous decline of nigral dopamine cell function following destruction of their intrinsic striatal target neurons. The results of our experience to date in PET studies of 6-[18F]fluoro-L-dopa and [76Br]bromolisuride binding in IA-lesioned primates indicate that PET can identify effects of cell loss on markers of pre- and postsynaptic function in the striatum of living subjects.
Hantraye
P
P
URA CNRS 1285, Orsay, France.
Loc'H
C
C
Maziere
B
B
Khalili-Varasteh
M
M
Crouzel
C
C
Fournier
D
D
Yorke
J C
JC
Stulzaft
O
O
Riche
D
D
Isacson
O
O
D000818:Animals; D001692:Biological Transport; D001967:Bromine Radioisotopes; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism; D005462:Fluorine Radioisotopes; D007051:Ibotenic Acid / Q000633:toxicity*; D007700:Kinetics; D008090:Lisuride / Q000031:analogs & derivatives* / Q000378:metabolism; D010215:Papio; D011699:Putamen / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2; D014055:Tomography, Emission-Computed
D001967:Bromine Radioisotopes; D005462:Fluorine Radioisotopes; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D007051:Ibotenic Acid; C029112:5-fluorodopa; D004295:Dihydroxyphenylalanine; D008090:Lisuride; C039667:bromerguride