Astatine-211-labeled aza-vesamicol derivatives as sigma receptor ligands for targeted alpha therapy

Introduction: As sigma receptors are abundantly expressed on different types of cancer cells, several radiolabeled sigma receptor ligands have been developed for cancer imaging and therapy. Previously, we synthesized and evaluated radioiodinated aza-vesamicol derivatives, [¹²⁵I]pIC₃NV, [¹²⁵I]mIC₂N5V, and [¹²⁵I]mIC₃N5V. They accumulated in tumors, and [¹²⁵I]mIC₂N5V and [¹²⁵I]mIC₃N5V showed higher tumor to non-target tissue ratios than [¹²⁵I]pIC₃NV. Therefore, we synthesized and evaluated the corresponding ²¹¹At-labeled compounds, [²¹¹At]mAtC₂N5V and [²¹¹At]mAtC₃N5V, for targeted alpha therapy (TAT).

Methods: [²¹¹At]mAtC₂N5V and [²¹¹At]mAtC₃N5V were prepared by the standard method of electrophilic astatodestannylation of the corresponding trimethylstannyl precursors. Cellular uptake experiments, and biodistribution experiments and therapeutic experiments in tumor-bearing mice were performed.

Results: The radiochemical yields of [²¹¹At]mAtC₂N5V and [²¹¹At]mAtC₃N5V were 45.5 ± 14.4% and 56.9 ± 13.8%, respectively. After HPLC purification, their radiochemical purities were over 95%. [²¹¹At]mAtC₂N5V and [²¹¹At]mAtC₃N5V showed high uptake in DU-145 cells. They demonstrated high accumulation in tumors (6.9 ± 1.4%injected dose/g and 5.1 ± 1.4%injected dose/g at 1 h, respectively) and similar biodistribution tendencies compared with the corresponding ¹²⁵I-labeled compounds. A single injection of [²¹¹At]mAtC₂N5V (0.48 MBq) or [²¹¹At]mAtC₃N5V (0.48 MBq) significantly inhibited tumor growth.

Conclusion: These results indicated that [²¹¹At]mAtC₂N5V and [²¹¹At]mAtC₃N5V could be potential candidates for TAT.