Production of [(211)At]-astatinated radiopharmaceuticals and applications in targeted α-particle therapy

Abstract

(211)At is a promising radionuclide for α-particle therapy of cancers. Its physical characteristics make this radionuclide particularly interesting to consider when bound to cancer-targeting biomolecules for the treatment of microscopic tumors. (211)At is produced by cyclotron irradiation of (209)Bi with α-particles accelerated at ~28 MeV and can be obtained in high radionuclidic purity after isolation from the target. Its chemistry resembles iodine, but there is also a tendency to behave as a metalloid. However, the chemical behavior of astatine has not yet been clearly established, primarily due to the lack of any stable isotopes of this element, which precludes the use of conventional analytical techniques for its characterization. There are also only a limited number of research centers that have been able to produce this element in sufficient amounts to carry out extensive investigations. Despite these difficulties, chemical reactions typically used with iodine can be performed, and a number of biomolecules of interest have been labeled with (211)At. However, most of these compounds exhibit unacceptable instability in vivo due to the weakness of the astatine-biomolecule bond. Nonetheless, several compounds have shown high potential for the treatment of cancers in vitro and in several animal models, thus providing a promising basis that has allowed initiation of the first two clinical studies.

FIG. 1.

Simplified decay scheme of ²¹¹At.

FIG. 2.

Cross-section of the irradiation of ²⁰⁹Bi as a function of the alpha particles energy. Plotted from the experimental data from Hermanne et al.

FIG. 3.

Example of a typical furnace used for the distillation of ²¹¹At. (A) Gas inlet with desiccant. (B) Furnace heated to 650°C–900°C. (C) Capillary trap cooled in (D) a dry ice/ethanol bath. It can be replaced by a cooled bubbler containing the solvent of interest. (E) Gas-wash bottle containing a reducing agent such as Na₂S₂O₅ to trap traces of astatine that would escape from the capillary. Reprinted by permission from Lindegren et al.

FIG. 4.

²¹¹At-M(16-S4-diol) complex, with M=Rh(III) or Ir(III).

FIG. 5.

Organic ligands investigated for the complexation of ²¹¹At discussed in the text.

FIG. 6.

Main reaction pathways used for the formation of a C–At bond.

FIG. 7.

Two possible dediazoniation pathways: (a) homolytic cleavage and (b) heterolytic cleavage.

FIG. 8.

Synthesis of meta-[²¹¹At]astatobenzylguanidine (MABG) via a supported tin precursor.

FIG. 9.

Preparation of a nido-carborane precursor and its radiolabeling with ²¹¹At⁺.

FIG. 10.

Uptake of ²¹¹At and ¹³¹I in normal mice 1 hour postdual injection of [²¹¹At]astatide and [¹³¹I]iodide. Chart plotted with data from Larsen et al.

FIG. 11.

Standard indirect labeling procedure for the astatination of proteins via the preparation of succinimidyl astatobenzoate (SAB).

FIG. 12.

Comparative biodistribution of [²¹¹At]-astatinated and [¹³¹I]-iodinated full antibody C110 IgG (A) with its F(ab′)₂ fragment (B) in mice. Charts plotted from data by Garg et al.

FIG. 13.

Modified prosthetic groups based on the SAB structure.^,–

FIG. 14.

Successive improvements to the biotin to increase the astatination stability.^–

FIG. 15.

Examples of small astatinated molecules unstable in vivo.^,,

FIG. 16.

Small molecules stable in vivo.^,