Production of [²¹¹At]-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.

Prostate-Specific Membrane Antigen–Targeted Radiohalogenated PET and Therapeutic Agents for Prostate Cancer

“…That observation, in concert with increased 211 At levels in tissues known to accumulate free halides (stomach and thyroid), suggested that some deastatination of 211 At-DCAtBzL had occurred. Nonetheless, these results are highly encouraging, particularly for a non-protein-based agent, because-to the best of our knowledge-that uptake is the highest level of sustained tumor uptake that has been reported for a 211 At-labeled targeted radiotherapeutic agent (58).…”

Bifunctional aryliodonium salts for highly efficient radioiodination and astatination of antibodies

“…1 On the other hand, 211 At is one of the most promising radionuclides for targeted α-particle therapy, and a growing number of [ 211 At]astatinated antibodies and derivatives are being investigated for cancer treatment. 2 …”

(2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy

“…In addition to the ALSYMPCA trial for CRPC, a-particle emitters have been investigated in other clinical trials and have consistently shown only mild toxicities (15). Among the a-emitters, 211 At has particularly favorable characteristics for clinical development including a 7.2-h half-life that is well matched to small-molecule therapeutics (16). A detailed review (17) summarizes the current status of 211 At-labeled radiotherapeutics and the importance for understanding the microscale distribution of a-emitters to predict toxicity and efficacy, an essential aspect of our studies.…”