[TC-99M]TRODAT-1 - A NOVEL TC-99M COMPLEX AS A DOPAMINE TRANSPORTER IMAGING AGENT

Technetium-99m is the most commonly used radionuclide in routine nucle ar medicine imaging procedures. Development of Tc-99m-labeled receptor -specific imaging agents for studying the central nervous system is po tentially useful for evaluation of brain function in normal and diseas e states. A novel Tc-99m-labeled tropane derivative, [Tc-99m]TRODAT-1, which is useful as a potential CNS dopamine transporter imaging agent , was evaluated and characterized. After i.v. injection into rats, [Tc -99m]TRODAT-1 displayed specific brain uptake in the rat striatal regi on (striatum-cerebellum/cerebellum ratio 1.8 at 60 min), where dopamin e neurons are concentrated. The specific striatal uptake could be bloc ked by pretreating rats with a dose of competing dopamine transporter ligand, beta-CIT (or RTI-55, i.v., 1 mg/kg). However, the specific str iatal uptake of [Tc-99m]TRODAT-1 was not affected by co-injection of e xcess fi-ee ligand (TRODAT-1, up to 200 mu g per rat) or by pretreatin g the rats with haloperidol (i.v., 1 mg/kg), The specific uptake in st riatal regions of rats that had prior 6-hydroxydopamine lesion in the substantia nigra area showed a dramatic reduction. The radioactive mat erial recovered from the rat striatal homogenates at 60 min after i.v. injection of [Tc-99m]TRODAT-1 showed primarily the original compound (> 95%), a good indication of in vivo stability in brain tissue. Simil ar and comparable organ distribution patterns and brain regional uptak es of [Tc-99m]TRODAT-1 were obtained for male and female rats. Ex vivo autoradiography results of rat brain sections further confirmed the h igh uptake and retention of [Tc-99m]TRODAT-1 in the striatal region. I n vitro binding studies measuring the affinity to dopamine transporter s for the free ligand, TRODAT-1, and a nonradioactive rhenium derivati ve, Re-TRODAT-1, showed K-i values of 9.7 nM and 14.1 nM, respectively . Behavioral studies in rats using the free ligand, TRODAT-1 and Re-TR ODAT-1 indicated that, unlike other tropane derivatives, they displaye d no effect on locomotor activity, suggesting low toxicity. These resu lts strongly support the conclusions that this novel Tc-99m radioligan d binds selectively to dopamine transporters in the brain and that is is potentially useful for in vivo assessment of the loss of dopamine n eurons in Parkinson's and other neurodegenerative diseases.