Production, purification and availability of 211At: Near term steps towards global access

Abstract

The promising characteristics of the 7.2-h radiohalogen ²¹¹At have long been recognized; including having chemical properties suitable for labeling targeting vectors ranging from small organic molecules to proteins, and the emission of only one α-particle per decay, providing greater control over off-target effects. Unfortunately, the impact of ²¹¹At within the targeted α-particle therapy domain has been constrained by its limited availability. Paradoxically, the most commonly used production method - via the ²⁰⁹Bi(α,2n)²¹¹At reaction - utilizes a widely available natural material (bismuth) as the target and straightforward cyclotron irradiation methodology. On the other hand, the most significant impediment to widespread ²¹¹At availability is the need for an accelerator capable of generating ≥28 MeV α-particles with sufficient beam intensities to make clinically relevant levels of ²¹¹At. In this review, current methodologies for the production and purification of ²¹¹At - both by the direct production route noted above and via a ²¹¹Rn generator system - will be discussed. The capabilities of cyclotrons that currently produce ²¹¹At will be summarized and the characteristics of other accelerators that could be utilized for this purpose will be described. Finally, the logistics of networks, both academic and commercial, for facilitating ²¹¹At distribution to locations remote from production sites will be addressed.

Keywords: Alpha emitter; Astatine; Cyclotron; Radionuclide production; Targeted alpha-particle therapy.

Figure 1.

Simplified ²¹¹At decay scheme illustrating double-branched pathway; by direct alpha decay to ²⁰⁷Bi and by electron capture to ²¹¹Po followed by alpha decay to ²⁰⁷Pb.

Figure 2.

Cross sections for the production of ²¹¹At and ²¹⁰At by bombardment of natural bismuth targets via the ²⁰⁹Bi(α,2n)²¹¹At and ²⁰⁹Bi(α,3n)²¹⁰At nuclear reactions, respectively, as a function of incident α-particle beam energy (E_α). Data from Experimental Nuclear Reaction Data (EXFOR https://www-nds.iaea.org/exfor/), reported by Hermanne et al., 2005) and Lambrecht and Mirzadeh, 1985.

Figure 3.

Irradiation parameters utilized at the 3 institutes currently having the highest ²¹¹At production capability.

Figure 4.

Production of ²¹¹At at the PET and Cyclotron Unit, Rigshospitalet, Copenhagen, Denmark. The Bi target is placed on a water-cooled probe at a grazing angle on beam contact. Following transport to Gothenberg, Sweden, a dry distillation apparatus is used for the purification of ²¹¹At.

Figure 5.

Illustration of the ²¹¹At production and purification methods utilized at the Duke University Medical Center. The production of ²¹¹At is accomplished using an internal target system and ²¹¹At is isolated from the bismuth target by dry distillation. After elution from PTFE in the required solvent, the ²¹¹At is available for use in radiolabeling procedures.

Figure 6.

The ²¹¹At production and purification process at the University of Washington Medical Center. An external target is placed at a slanted angle in the pneumatic target system. An automatic system was developed to dissolve the target material and purify ²¹¹At using a wet chemistry method.

Figure 7.

Optimization of ⁷Li beam energy and cooling period for the production of ²¹¹Rn. A) Estimated yields of ²¹¹Rn and ²¹⁰Rn in a thick Bi target after a 1-h irradiation at a beam intensity of 1 μAp. B) The radioactivity ratio of ²¹¹At and ²¹⁰At during the cooling period. Data kindly provided by Professor Akihiko Yokoyama (Kanazawa University, Japan). C) Possible impurities.

Figure 8.

Two potential distribution models for ²¹¹At: A) Centralized distribution where formulated radiopharmaceuticals are distributed to hospitals within a feasible distance radius; B) De-centralized distribution where irradiated targets containing ²¹¹At are distributed to hub-facilities with a GMP radiochemistry lab and ²¹¹At radiopharmaceuticals are formulated there before distribution to hospitals.