Masayuki Munekane, Takeshi Fuchigami, Kazuma Ogawa
High-linear energy transfer (high-LET) radiation offers a promising strategy to overcome the limitations of conventional β − -emitters in resistant or heterogeneous tumors. This review highlights recent advances in high LET radiotheranostics from a coordination chemistry perspective, focusing on α-emitters ( 225 Ac, 227 Th, 212/213 Bi, and 212 Pb) and Auger electron-emitters ( 161 Tb, 64 Cu, and 191/193m/195m Pt). Therapeutic performance is governed by intrinsic metal ion properties, including ionic radius, charge density, and donor preference, which dictate complex stability, kinetic inertness, and resistance to recoil during decay. The large Ac 3+ ion requires high denticity chelators for efficient radiolabeling and in vivo stability, while recoil of daughter radionuclides ( 221 Fr, 213 Bi) remains a major redistribution challenge that has motivated nanoparticle and liposomal strategies. 227 Th forms stable complexes with 1-hydroxy-2(1H)-pyridinones (1,2-HOPO)-type ligands for antibody delivery, although bone-seeking 223 Ra generation must be considered. Short-lived 212 Bi/ 213 Bi and the 212 Pb/ 212 Bi in vivo generator system demand rapid labeling and appropriate pharmacokinetics, and ligands such as OCTAPA or DOTAM (TCMC) better match the coordination preferences of Bi(III) and Pb(II). Although 212 Pb enables element matched 203 Pb/ 212 Pb theranostics, daughter redistribution remains challenging. For Auger emitters, efficacy depends not only on complex stability but also on controlled intracellular localization. The coordination chemistry of Tb(III), Cu(II), and Pt(II) governs chelator selection and subcellular fate, as illustrated by [ 161 Tb]Tb-DOTA conjugates, stable 64 Cu complexes, and DNA targeting radioplatinum agents. Overall, this review establishes coordination-driven design principles for high-LET radiotheranostics, bridging inorganic chemistry and translational nuclear medicine toward next-generation precision radiotherapy.