Harnessing alpha-emitting radionuclides for therapy: radiolabeling method review.

Targeted alpha therapy (TAT) is an emerging and powerful tool for treating late-stage cancers for which therapeutic options are limited. At the core of TAT is the development of targeted radiopharmaceuticals, where isotopes are paired with biological targeting vectors that enable tissue- or cell-specific delivery of alpha-emitters. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and diethylenetriamine pentaacetic acid (DTPA) are commonly used to chelate metallic radionuclides, but have several limitations. Significant efforts are underway to develop effective and stable chelators for alpha-emitters and are at various stages of development and community adoption. Isotopes such as 149Tb, 212/213Bi, 212Pb (for 212Bi), 225Ac, 226/227Th have identified suitable chelators, although further studies, especially in vivo studies, are required; while for others, including 223Ra, 230U, and arguably 211At an ideal chelate remains elusive. In this review, we will summarize the chelation chemistry 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.