TC-99M-LABELED TROPANES AS DOPAMINE TRANSPORTER IMAGING AGENTS

The development of novel Tc-99m-labeled tropane derivatives as dopamin e transporter imaging agents is reported. A series of neutral and lipo philic conjugated complexes, containing N-(alkylthiolato)tropane, amin obis(ethylthiolato), and a [(TC)-T-99m]TcO3+ center core, were prepare d and evaluated as central nervous system (CNS) dopamine transporter i maging agents in rats. One of the compounds, [Tc-99m]technetium, [meth yl oxylato-S][[2,2'-(methylimino)bis[ethanethiolato]] (2-)-N,S,S']oxo (25), displayed low initial uptake in rat brain (0.1% at 2 min post iv injection); the striatal/cerebellar (ST/CB) ratio reached 3.50 at 60 min after an iv injection. The specific uptake can be blocked by pretr eating rats with a competing dopamine transporter binding agent, beta- CIT (RTI-55, N-methyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ; iv; 1 mg/kg), which reduced the regional brain uptake ratio (ST/CB) to 1.0. In contrast, the specific uptake in striatum was not affected by pretreating rats with a noncompeting ligand, haldol (iv, 1 mg/kg). In vitro autoradiography of rat brain sections exhibited elevated labe ling in striatum, major islands of Calleja, and olfactory tubercle reg ions, where dopamine neurons are known to be concentrated. This series of compounds is the first example of technetium-99m labeled CNS recep tor-specific imaging agents and may provide a convenient source of sho rt-lived imaging agents for routine diagnosis of CNS abnormality in co njunction with single photon emission computed tomography.