Macropa derivatives for radiopharmaceutical and rare-earth element separation.

Recognition of large f-block ions underlies advances in targeted radionuclide therapy and rare-earth element separations. Like the lanthanide-binding protein lanmodulin, the 18-membered macrocycle macropa displays reverse-size selectivity characterized by its preference for binding large metal ions. Its diaza-18-crown-6 scaffold enables efficient complexation of therapeutically relevant radiometals, such as 225Ac, 223Ra, and 213Bi, while accommodating diagnostic partners, including 203Pb and radiolanthanides. In parallel, systematic differences in stability constants across the lanthanide series enable size-based discrimination in separation chemistry. Macropa and its derivatives have been deployed in different strategies to recover and purify rare-earth elements and minor actinides. This manuscript describes recent studies on modifications of macropa, including cavity expansion, alteration of donor atoms, backbone rigidification, chelator-embedded 18F incorporation, and acyclic variants to demonstrate that effective selectivity arises from balancing preorganization, donor strength, and conformational adaptability. These studies establish macropa-based scaffolds as synthetic systems that bridge radiopharmaceutical coordination chemistry and rare-earth element separations.