A Technetium-99m SPECT Imaging Agent Which Targets the Dopamine Transporter in Primate Brain

Abstract

The dopamine transporter (DAT), located presynaptically on dopamine neurons, provides a marker for certain neurological diseases. In particular, the DAT is depleted in Parkinson's disease, and the extent of depletion correlates with the loss of dopamine. Herein we describe the design, synthesis, and biological evaluation of technepine, the first 99mTc-labeled SPECT imaging agent which targets the dopamine transporter in striatum. We have demonstrated that the DAT can accommodate a chelating unit attached to the 8-amine function of a tropane skeleton. Further, we have demonstrated for the first time that a molecule can be designed to carry the radionuclide 99mTc across the blood-brain barrier in sufficient quantity to obtain in vivo images of the striatum in monkeys. This advance will undoubtedly lead to the design of new receptor and transporter-mediated 99mTc agents which can label specific transporter and receptor targets in the central nervous system.

Preparation of a technetium‐99m SPECT agent for imaging the sigma‐2 receptor status of solid tumors

“…This is consistent with the results obtained by Meltzer et al for the synthesis of the rhenium-complex of technepine. 10 The syn relationship between the Re¼O core and the N-alkyl substituent was confirmed by X-ray crystallography (Figure 2).…”

“…Removal of the N-benzyl group via catalytic dehydrogenation afforded the secondary amine, 5, in quantitative yield. Treatment of 10 afforded the corresponding rhenium complex, Re-2, in an overall yield of 45% that was exclusively the syn isomer. This is consistent with the results obtained by Meltzer et al for the synthesis of the rhenium-complex of technepine.…”

“…The N 2 S 2 chelate, 6, was prepared using the procedure outlined in Scheme 1. 10 Radiolabeling with 99m Tc was accomplished using acidic conditions with Sn-glucoheptonate and [ …”

“…The popularity of this radionuclide stems from the low cost and widespread availability of the 99 Mo/ 99m Tc generator, its medium gamma ray energy (140 keV) which is suitable for gamma camera detection, and its physical half-life (t 1=2 ¼ 6 h) which is convenient for image acquisition. A number of recent studies have indicated that it is possible to prepare 10 have been shown to possess a high affinity for the dopamine transporter ( Figure 1). These studies suggest the feasibility of preparing a small molecule based 99m Tc-labeled radiotracer for imaging s 2 receptors provided that there is a suitable lead compound for radiotracer development.…”

Design of a radiopharmaceutical for the palliation of painful bone metastases: rhenium‐186‐labeled bisphosphonate derivative

“…16 Compound 2 (100 mg, 0.15 mmol) was suspended in 2 ml of ethanol. SnCl 2 Á 2H 2 O (31 mg, 0.14 mmol) in 0.5 ml of 0.1 N HCl and KReO 4 (40 mg, 0.14 mmol) in 0.5 ml of 0.1 N HCl were added to this stirred suspension, then this reaction mixture was refluxed at 1208C for 12 h. After the solvent was removed in vacuo, the residue was purified by RP-HPLC performed with a Cosmosil 5C 18 -AR-300 column (10 Â 150 mm) at a flow rate of 4.7 ml/min with a gradient mobile phase from 95% A (0.1% aqueous TFA) and 5% B (acetonitrile with 0.1% TFA) to 100% B in 30 min.…”