Harnessing α-Emitting Radionuclides for Therapy: Radiolabeling Method Review

Targeted α-therapy (TAT) is an emerging powerful tool treating late-stage cancers for which therapeutic options are limited. At the core of TAT are targeted radiopharmaceuticals, where isotopes are paired with targeting vectors to enable tissue- or cell-specific delivery of α-emitters. DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and DTPA (diethylenetriamine pentaacetic acid) are commonly used to chelate metallic radionuclides but have limitations. Significant efforts are underway to develop effective stable chelators for α-emitters and are at various stages of development and community adoption. Isotopes such as ¹⁴⁹Tb, 212/213Bi, ²¹²Pb (for ²¹²Bi), ²²⁵Ac, and 226/227Th have found suitable chelators, although further studies, especially in vivo studies, are required. For others, including ²²³Ra, ²³⁰U, and, arguably ²¹¹At, the ideal chemistry remains elusive. This review summarizes the methods reported to date for the incorporation of ¹⁴⁹Tb, ²¹¹At, 212/213Bi, ²¹²Pb (for ²¹²Bi), ²²³Ra, ²²⁵Ac, 226/227Th, and ²³⁰U into radiopharmaceuticals, with a focus on new discoveries and remaining challenges.