An automated process for astatine-211 isolation from irradiated bismuth targets using a tellurium-packed column

Objectives: The objective of this research effort was to evaluate automation of a facile method for isolation of ²¹¹At from irradiated bismuth targets using tellurium-packed columns (Te-column). ²¹¹At is an attractive radionuclide for targeted alpha therapy (TAT) due to its physical properties; 7.21 h half-life, minimal high energy gamma-ray emission and 100% alpha emission. Highly efficient and robust automated ²¹¹At isolation systems are required for improving its availability and to facilitate clinical studies of ²¹¹At-labeled TAT agents.

Methods: Chromatographic conditions for manually separating ²¹¹At using Te-columns were optimized using small amounts, i.e. ≤37 MBq (≤1 mCi), of ²¹¹At based on the early studies of Bochvarova and co-workers¹. In evaluations of the automated system, targets containing ~0.96 GBq (~26 mCi) of ²¹¹At were dissolved in 10 M HNO₃ using an in-line dissolution chamber² and the resultant solution was routed into a 250-mL reaction vessel. Then an NH₂OH·HCl solution was added dropwise into the reaction vessel to destroy the nitrate ions, followed by a HCl solution to reconstitute the ²¹¹At/Bi mixture to 1.5 M HCl solution. Subsequently, the Te-column was loaded with the ²¹¹At/Bi mixture, washed with 1.5 M HCl and H₂O. Finally, ²¹¹At was eluted using 5 mL of 2 M NaOH. In the automated system, Hamilton Microlab 500 Series Diluter/Dispenser dual-syringe pump and Modular Valve Positioners controlled by the Microlab 500 Control Software were used for routing and delivering all the liquids. The radiochemical purity of the ²¹¹At was assessed using radio-HPLC and radio-iTLC. The ²¹¹At obtained was used to radiolabel isothiocyanato-phenethyl-closo-decaborate(2-) (B10-NCS)-conjugated antibodies after adjusting the pH to ~7.0. The concentrations of Bi and Te in ²¹¹At solutions and astatinated antibodies were determined using ICP-MS. Results: The automated isolation process took less than 2 h, and ²¹¹At isolated yields (after attenuation and decay correction) of 88-95% were achieved. Radio-HPLC analyses showed that ≥ 99% of the ²¹¹At in the final product was astatide. Astatination yields of B10-conjugated antibody were high (77-95%) and the concentration of Bi and Te in the size-exclusion column purified final product was less than 0.031 and 0.19 ppm, respectively. Conclusions: An efficient automated process that uses Te-columns for separating ²¹¹At from irradiated Bi targets has been developed. The purified ²¹¹At is of high radiochemical purity and suitable for B10-conjugated antibody astatination reactions. Acknowledgments: The authors gratefully acknowledge the staff of the U.W. Medical Cyclotron Facility, especially E.F. Dorman and R.C. Emery, for assistance in obtaining irradiated bismuth targets. We thank the Isotope Research & Development program, Office of Science, United States Department of Energy for funding this research (DE-SC0013618 & DE-SC0018013). References: 1. M. Bochvarova, D. K. T., I. Dudova, Yu. V. Norseev, and V. A. Khalkin, Investigation of Columns Filled with Crystalline Tellurium for the Production of Radiochemically Pure Preparations of Astatine. Translated from Radiokhimiya 1972, 14 (6), 858-865. 2. O’Hara, M. J., Krzysko, A. J., Niver, C. M., Morrison, S. S., Owsley, S. L., Hamlin, D. K., Dorman, E. F., and Wilbur, D.S, An automated flow system incorporating in-line acid dissolution of bismuth metal from a cyclotron irradiated target assembly for use in the isolation of astatine-211. Applied Radiation and Isotopes 2017, 122 (Supplement C), 202-210.