QUANTIFICATION OF DOPAMINE TRANSPORTER DENSITY IN MONKEYS BY DYNAMIC PET IMAGING OF MULTIPLE INJECTIONS OF C-11 CFT

Idiopathic Parkinson's disease (PD) is characterized by loss of dopami nergic 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 di sease progression. In this study, we evaluated [C-11] 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 a nimals was studied after treatment with the neurotoxin, MPTP. Simulati on studies demonstrated that a three injection protocol is necessary f or quantitation of dopamine transporter density. The protocol consists of an initial high specific activity injection, a low specific activi ty ''displacement dose'' at 30 min, and a final high specific activity injection at similar to 90 min. Dynamic PET imaging and arterial bloo d sampling were started immediately before the first injection and con tinued for 2 h. Blood data were corrected for [C-11] labeled CFT metab olites. Compartmental models describing the dynamics of labeled and th e unlabeled ligand explicitly were fitted to the PET and metabolite co rrected 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 K-D = 33 nM (n = 3). These values for B'(max ) are in reasonable agreement with published values for [H-3] CFT bind ing 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. K-D wa s relatively unaffected by MPTP treatment. These data provide addition al basis for the use of [C-11] CFT in monitoring the progression of Pa rkinson's disease and other conditions that are associated with the lo ss of dopaminergic nerve terminals. (C) 1996 Wiley-Liss, Inc.