Realizing Clinical Trials with Astatine-211: The Chemistry Infrastructure

Abstract

Despite the consensus around the clinical potential of the α-emitting radionuclide astatine-211 (²¹¹At), there are only a limited number of research facilities that work with this nuclide. There are three main reasons for this: (1) Scarce availability of the nuclide. Despite a relatively large number of globally existing cyclotrons capable of producing ²¹¹At, few cyclotron facilities produce the nuclide on a regular basis. (2) Lack of a chemical infrastructure, that is, isolation of ²¹¹At from irradiated targets and the subsequent synthesis of an astatinated product. At present, the research groups that work with ²¹¹At depend on custom systems for recovering ²¹¹At from the irradiated targets. Setting up and implementing such custom units require long lead times to provide a proper working system. (3) The chemistry of ²¹¹At. Compared with radiometals there are no well-established and generally accepted synthesis methods for forming sufficiently stable bonds between ²¹¹At and the tumor-specific vector to allow for systemic applications. Herein we present an overview of the infrastructure of producing ²¹¹At radiopharmaceuticals, from target to radiolabeled product including chemical strategies to overcome hurdles for advancement into clinical trials with ²¹¹At.

Keywords: astatine-211; targeted α; therapy.

FIG. 1.

Physical properties of ²¹¹At. Color images are available online.

FIG. 2.

The chemical infrastructure for production of ²¹¹At radiopharmaceuticals. Color images are available online.

FIG. 3.

Examples of different aryl functional groups for ²¹¹At substitution reactions. From top: Iodine, isotope exchange; diazonium salt; aryliodonium salt; aryl tin; aryl boron pinnacol ester; aryl tin with guanidine moiety.

FIG. 4.

Methods for astatine labeling through a bifunctional reagent carrying an N-succinimidyl ester group for conjugation and a reactive group Y for astatination. (1) Two-step radiochemical reaction, labeling of the reagent followed by astatination. (2) One-step radiochemical reaction, conjugation of the reagent followed by astatination of the conjugate.