Novel technetium-99m-labelled dihydrotetrabenazine derivative as a vesicular monoamine transporter 2 probe: synthesis and preliminary biological evaluation

Introduction: The vesicular monoamine transporter 2 (VMAT2) is highly expressed in the brain striatum and pancreatic b-cells. VMAT2 dysfunction associates with many disorders, including Parkinson’s disease (PD), diabetes mellitus and some others. Non-invasive VMAT2 imaging is available for early clinical diagnosis, classification and treatment monitoring of the related diseases. The development of technetium-99m-labelled dihydrotetrabenazine (DTBZ) derivative for 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. The objective of this study was to synthesize and evaluate its to develop a potential SPECT probe for monitoring VMAT2 binding sites.

Methods: 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.-bisaminodithiol-propyl-dihydrotetrabenazine ([^99mTc]Tc-BAT-P-DTBZ) was obtained by a simple ligand exchange reaction and examined in terms of radiochemical purity, stability and lipophilicity. The biological activity of was further evaluated by in vitro , and regional brain biodistribution studies.

Results: Under the optimized labelling condition, [^99mTc]Tc-BAT-P-DTBZ was acquired with a good radiochemical purity of above 95%. The quality control test showed that is stable over 6 h and it has a suitable lipophilicity (LogP_7.4 = 1.69), suggesting successful appositeness for the needs of routine biological evaluation experiments. The in vitro homogenate binding revealed that could bind to VMAT2 sites. The ex vivo biodistribution study clearly indicated that the (VMAT2-enriched region) displays relatively high uptake (, n = 5) of among all organs in the mice body and the pancreas uptake could be partially blocked (~30%; p < 0.01, n = 5) by the competing dose of DTBZ (2 mg/kg). The regional brain biodistribution in SD rats implied the inability of[^99mTc]Tc-BAT-P-DTBZ to penetrate the blood-brain barrier.

Conclusions: was successfully designed and prepared in this study. The preliminary biological evaluation indicated that has a potential for non-invasive assessment of VMAT2 in pancreas or other non-brain organs.

Acknowledgements: The present work was supported by the Research Foundation of Jiangsu Provincial Commission of Health (M2022047), the National Natural Science Foundation of China (82172054) and the Natural Science Foundation of Jiangsu Province (BK20201133, BK20210062).