Derivatization of dihydrotetrabenazine for technetium-99m labelling towards a radiotracer targeting vesicular monoamine transporter 2

Abstract

The development of technetium-99m-labelled dihydrotetrabenazine (DTBZ) derivative for vesicular monoamine transporter 2 (VMAT2) tracing could be a benefit for single photon emission computed tomography (SPECT) imaging due to easy labelling chemistry and great availability through nuclide generator system. Here, we successfully prepared a technetium-99m-labelled DTBZ derivative and subsequently evaluated its biological activity targeting VMAT2. A novel combination of the bisaminoethanethiol (BAT) chelator scaffold with the biologically active DTBZ vector was performed to synthesize the labelling precursor BAT-P-DTBZ, and it was accomplished in six steps. The technetium-99m labelling was carried out in the radiochemical study of BAT-P-DTBZ conjugate, and the radiolabelling conditions were investigated and optimized. Under the optimized labelling condition, 99mTc-BAT-P-DTBZ was acquired with a good radiochemical purity of above 95 %. The quality control test showed that 99mTc-BAT-P-DTBZ is stable over 6 h and it has a suitable lipophilicity, suggesting successful appositeness for the needs of routine biological evaluation experiments. The in vitro biological evaluation revealed that 99mTc-BAT-P-DTBZ could bind to VMAT2 sites. The in vivo biodistribution study clearly indicated that the pancreas (VMAT2-enriched region) displays relatively high uptake of 99mTc-BAT-P-DTBZ among all organs in mice. The specific VMAT2 binding signal of 99mTc-BAT-P-DTBZ was separately detected in the in vitro and in vivo biological evaluation. Therefore, 99mTc-BAT-P-DTBZ might be a potential imaging agent for monitoring VMAT2 binding sites in the pancreas.

Keywords

• Dihydrotetrabenazine
• Bisaminobisthiol
• Technium-99m
• Vesicular monoamine transporter 2