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.