Increasing access to the short-lived α-emitting radionuclide astatine-211 (²¹¹At) has the potential to advance targeted α-therapeutic treatment of disease and to solve challenges facing the medical community. For example, there are numerous technical needs associated with advancing the use of ²¹¹At in targeted α-therapy, e.g., improving ²¹¹At chelates, developing more effective ²¹¹At targeting, and characterizing in vivo²¹¹At behavior. There is an insufficient understanding of astatine chemistry to support these efforts. The chemistry of astatine is one of the least developed of all elements on the periodic table, owing to its limited supply and short half-life. Increasing access to ²¹¹At could help address these issues and advance understanding of ²¹¹At chemistry in general. We contribute here an extraction chromatographic processing method that simplifies ²¹¹At production in terms of purification. It utilizes the commercially available Pre-Filter resin to rapidly (<1.5 h) isolate ²¹¹At from irradiated bismuth targets (Bi decontamination factors ≥876 000), in reasonable yield (68–55%) and in a form that is compatible for subsequent in vivo study. We are excited about the potential of this procedure to address ²¹¹At supply and processing/purification problems.

Cyclotron-produced astatine-211 (²¹¹At) shows tremendous promise in targeted alpha therapy (TAT) applications due to its attractive half-life and its 100% α-emission from nearly simultaneous branched alpha decay. Astatine-211 is produced by alpha beam bombardment of naturally monoisotopic bismuth metal (²⁰⁹Bi) via the (α, 2n) reaction. In order to isolate the small mass of²¹¹At (specific activity = 76 GBq·µg⁻¹) from several grams of acid-dissolved Bi metal, a manual milliliter-scale solvent extraction process using diisopropyl ether (DIPE) is routinely performed at the University of Washington. As this process is complex and time consuming, we have developed a fluidic workstation that can perform the method autonomously. The workstation employs two pumps to concurrently deliver the aqueous and organic phases to a mixing tee and in-line phase mixer. The mixed phases are routed to a phase settling reservoir, where they gravity settle. Finally, each respective phase is withdrawn into its respective pump. However, development of a phase boundary sensor, placed in tandem with the phase settling reservoir, was necessary to communicate to the system when withdrawal of the denser aqueous phase was complete (i.e., the intersection of the two phases was located). The development and optimization of the autonomous solvent extraction system is described, and the²¹¹At yields from several ~1.1 GBq-level²¹¹At processing runs are reported.

Astatine-211 is an attractive radionuclide for use in targeted alpha therapy of blood-borne diseases and micrometastatic diseases. Efficient isolation methods that can be adapted to robust automated ²¹¹At isolation systems are of high interest for improving the availability of ²¹¹At. Based on the early studies of Bochvarova and co-workers involving isolation of ²¹¹At from irradiated thorium targets, we developed a method for ²¹¹At isolation from bismuth targets using tellurium-packed columns. Dissolution of irradiated bismuth targets is accomplished using HNO₃; however, ²¹¹At is not captured on the Te column material in this matrix. Our method involves slow addition of aqueous NH₂OH·HCl to the Bi target dissolved in HNO₃ to convert to a HCl matrix. The amount of NH₂OH·HCl was optimized because (1) the quantity of NH₂OH·HCl used appears to affect the radiolabeling yield of phenethyl-closo-decaborate(2-) (B10)-conjugated antibodies and (2) reducing the volume of NH₂OH·HCl solution can effectively shorten the overall isolation time. A proof-of-concept semi-automated process has been demonstrated using targets containing ~0.96 GBq (~26 mCi) of ²¹¹At. High isolation yields (88–95%) were obtained. Radiochemical purity of the isolated ²¹¹At was assessed by radio-HPLC. Concentrations of Bi and Te contaminants in the ²¹¹At and the astatinated antibodies were evaluated using ICP-MS.

The alpha particle-emitting radionuclide astatine-211 (²¹¹At) is of interest for targeted radiotherapy; however, low in vivo stability of many ²¹¹At-labeled cancer-targeting molecules has limited its potential. As an alternative labeling method, we evaluated whether a specific type of astatinated aryl compound that has the At atom in a higher oxidation state might be stable to in vivo deastatination. In the research effort, para-iodobenzoic acid methyl ester and dPEG₄-amino acid methyl ester derivatives were prepared as HPLC standards. The corresponding para-stannylbenzoic acid derivatives were also prepared and labeled with ¹²⁵I and ²¹¹At. Oxidization of the [¹²⁵I]iodo- and [²¹¹At]astato-benzamidyl-dPEG₄-acid methyl ester derivatives provided materials for in vivo evaluation. A biodistribution was conducted in mice with coinjected oxidized ¹²⁵I- and ²¹¹At-labeled compounds. The oxidized radioiodinated derivative was stable to in vivo deiodination, but unfortunately the oxidized [²¹¹At]astatinated benzamide derivative was found to be unstable under the conditions of isolation by radio-HPLC (post animal injection). Another biodistribution study in mice evaluated the tissue concentrations of coinjected [²¹¹At]NaAtO₃ and [¹²⁵I]NaIO₃. Comparison of the tissue concentrations of the isolated material from the oxidized [²¹¹At]benzamide derivative with those of [²¹¹At]astatate indicated the species obtained after isolation was likely [²¹¹At]astatate.