Quantification of dopamine transporter density in monkeys by dynamic PET imaging of multiple injections of 11C-CFT.
Idiopathic Parkinson's disease (PD) is characterized by loss of dopaminergic terminals in the basal ganglia. The cocaine analog, CFT (WIN 35,428), has been shown to bind selectively to the pre-synaptic dopamine transporters and thus represents an important probe for monitoring disease progression. In this study, we evaluated [11C] labeled CFT as a PET ligand for the quantitative in vivo assay of dopamine transporter density in three normal rhesus monkeys (Macaca mulatta). One of the animals was studied after treatment with the neurotoxin, MPTP. Simulation studies demonstrated that a three injection protocol is necessary for quantitation of dopamine transporter density. The protocol consists of an initial high specific activity injection, a low specific activity "displacement dose" at 30 min, and a final high specific activity injection at approximately 90 min. Dynamic PET imaging and arterial blood sampling were started immediately before the first injection and continued for 2 h. Blood data were corrected for [11C] labeled CFT metabolites. Compartmental models describing the dynamics of labeled and the unlabeled ligand explicitly were fitted to the PET and metabolite corrected blood data. Prior to MPTP treatment, modeling of the striatal data required a saturable receptor term and yielded mean estimates of: B'max = 113 pmol/g and KD = 33 nm (n = 3). These values for B'max are in reasonable agreement with published values for [3H] CFT binding in vitro. After multiple treatments with MPTP (0.6 mg/kg x 3), B'max in one of the animals was reduced from 122 to 10.2 pmol/g. KD was relatively unaffected by MPTP treatment. These data provide additional basis for the use of [11C] CFT in monitoring the progression of Parkinson's disease and other conditions that are associated with the loss of dopaminergic nerve terminals.
Morris
E D
ED
Department of Radiology, Massachusetts General Hospital, Boston 02114, USA.
Babich
J W
JW
Alpert
N M
NM
Bonab
A A
AA
Livni
E
E
Weise
S
S
Hsu
H
H
Christian
B T
BT
Madras
B K
BK
Fischman
A J
AJ
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D001923:Brain Chemistry / Q000187:drug effects*; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000378:metabolism*; D002531:Cerebellum / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D015259:Dopamine Agents / Q000633:toxicity; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D007553:Isotope Labeling; D020267:MPTP Poisoning; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008959:Models, Neurological; D009048:Motor Skills / Q000187:drug effects; D017072:Neostriatum / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D014055:Tomography, Emission-Computed
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011954:Receptors, Dopamine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine