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.