[99mTc]TRODAT-1: A novel technetium-99m complex as a dopamine transporter imaging agent

Abstract

Technetium-99m is the most commonly used radionuclide in routine nuclear medicine imaging procedures. Development of 99mTc-labeled receptor-specific imaging agents for studying the central nervous system is potentially useful for evaluation of brain function in normal and disease states. A novel 99mTc-labeled tropane derivative, [99mTc]TRODAT-1, which is useful as a potential CNS dopamine transporter imaging agent, was evaluated and characterized. After i. v. injection into rats, [99mTc]TRODAT-1 displayed specific brain uptake in the rat striatal region (striatum-cerebellum/cerebellum ratio 1.8 at 60 min), where dopamine neurons are concentrated. The specific striatal uptake could be blocked by pretreating rats with a dose of competing dopamine transporter ligand, beta-CIT (or RTI-55, i.v., 1 mg/kg). However, the specific striatal uptake of [99mTc]TRODAT-1 was not affected by co-injection of excess free ligand (TRODAT-1, up to 200 microg per rat) or by pretreating the rats with haloperidol (i.v., 1 mg/kg). The specific uptake in striatal regions of rats that had prior 6-hydroxydopamine lesion in the substantia nigra area showed a dramatic reduction. The radioactive material recovered from the rat striatal homogenates at 60 min after i.v. injection of [99mTc]TRODAT-1 showed primarily the original compound (>95%), a good indication of in vivo stability in brain tissue. Similar and comparable organ distribution patterns and brain regional uptakes of [99mTc]TRODAT-1 were obtained for male and female rats. Ex vivo autoradiography results of rat brain sections further confirmed the high uptake and retention of [99mTc]TRODAT-1 in the striatal region. In vitro binding studies measuring the affinity to dopamine transporters for the free ligand, TRODAT-1, and a nonradioactive rhenium derivative, Re-TRODAT-1, showed Ki values of 9.7 nM and 14.1 nM, respectively. Behavioral studies in rats using the free ligand, TRODAT-1 and Re-TRODAT-1 indicated that, unlike other tropane derivatives, they displayed no effect on locomotor activity, suggesting low toxicity. These results strongly support the conclusions that this novel 99mTc radioligand binds selectively to dopamine transporters in the brain and that is is potentially useful for in vivo assessment of the loss of dopamine neurons in Parkinson's and other neurodegenerative diseases.

No correlation between body mass index and striatal dopamine transporter availability in healthy volunteers using SPECT and [123I]PE2I

“…99m Tc]TRODAT-1, which also binds significantly to the serotonin transporter (SERT) (21,22). This is potentially important since striatal and thalamic SERT availability recently was shown to be negatively correlated to BMI in 60 subjects (23).…”

Recent Advances in Imaging of Dopaminergic Neurons for Evaluation of Neuropsychiatric Disorders

“…The technetium based 99m Tc-TRODAT-1 has the advantage of being relatively inexpensive and available in kit form. The easy preparation of 99m Tc-TRODAT-1 from lyophilized kits could be an ideal agent for daily clinical application [16]. However, its specific signal is lower than the 123 I-based SPECT tracers.…”

Considerations in the Development of Reversibly Binding PET Radioligands for Brain Imaging

“…Radioligands for use with SPECT are mostly labeled with γ-emitting iodine-123 ( t 1/2 = 13.2 h). Only rarely has technetium-99m ( t 1/2 = 6.0 h) been applied with some success [9, 10]. Both iodine-123 and technetium-99m are available commercially.…”