Coordination Chemistry of Emerging Meitner-Auger Electron-Emitting Radiometals for Targeted Radionuclide Therapy

Targeted radionuclide therapy (TRT) selectively delivers radionuclides to cancer cells, leveraging their radioactive emissions to treat primary and metastatic malignancies. Substantial fundamental research in this area has enabled the clinical development of a growing library of radiopharmaceuticals for this application, several of which have become blockbuster cancer drugs approved by the U.S. Food and Drug Administration. To date, these therapeutics have focused on radiometals emitting long-range β^- particles and shorter-ranged α particles. More recently, efforts to use a different type of cytotoxic radiation, Meitner-Auger electrons (MAEs), have been undertaken. MAEs are of interest for TRT because they travel very short distances-on the order of nanometers-that enable the possibility of single-cell and subcellular delivery of cytotoxic radiation. This high spatial precision is valuable for the treatment of diffuse malignancies such as lymphoma and leukemia, as well as for inducing unique cell death pathways with efficacy against conventional radiation resistance. As a number of emerging MAE-emitting radiometals are identified and produced, there is a need to develop suitable chelators that can form stable complexes with them so that they can be applied in targeted constructs. This review summarizes the coordination chemistry of emerging MAE-emitting radiometals, which span different regions of the Periodic Table, including the transition metals, main group elements, and lanthanides. In addition, approaches for their production and purification are also described. The major emphasis of this manuscript provides a summary of different chelators and chelation approaches for these novel MAE-emitting radiometals. This comprehensive summary of the coordination chemistry of these radiometals provides a guide for researchers in this area and emphasizes the chelator-design challenges that need to be overcome for their eventual clinical use.