The preclinical pharmacologic study of dopamine transporter imaging agent [99mTc]TRODAT-1

The purpose of this study was to investigate the pharmacologic characteristics of TRODAT-1 (2beta-((N,N'-bis(2-mercaptoethyl)ethylene diamino)methyl), 3beta-(4-chlorophenyl)tropane) labeled with [99mTc] as an imaging agent for dopamine transporter (DAT). Radiochemical purity of [99mTc]TRODAT-1 was over 90%. The partition coefficients in octanol and buffer were 2.12 and 2.19 at pH 7.0 and 7.4, respectively. Animal studies have been performed in rats, rabbits, and normal and hemi-Parkinsonian model monkeys. Biodistribution displayed moderate uptake in rat brain (0.28 %ID/organ at 2 min) and the striatal uptake was 0.193, 0.142, and 0.136 %ID/g at 2, 60, and 120 min, respectively. The ratios of striatal/cerebellar (ST/CB) uptake were 2.4, 4.45, and 2.45 %ID/g at 60, 120, and 240 min, respectively. The major radioactivity was excreted by the hepatobiliary system. Blood clearance kinetics was performed in rabbits, and the initial half-life of 1.18 min and late half-life of 367.8 min were obtained. Brain single photon emission computed tomography imaging studies in normal monkeys showed the ratios of ST/CB uptake were 1.56-2.0 %ID/g and indicated that both uptake and retention in the striatal area were associated with the DAT. The imaging of hemi-Parkinsonian model monkeys also displayed the expected selectivity, the highest uptake being observed in the basal ganglia area of the normal side. Thereby, it is suggested that [99mTc]TRODAT-1 is a safe and useful imaging agent for localization of the presynaptic DAT in the brain.