Designing Chelators for Large Radiometal Ions Relevant to Nuclear Medicine

Abstract

Targeted internal radiotherapy is an emerging modality in nuclear medicine that relies on the systemic administration of radiopharmaceutical agents. The use of α-particle–emitting radionuclides for this application is particularly attractive due to the high cytotoxic potency and short tissue penetration range of α particles. However, the clinical translation of therapeutic α-emitters has been limited in part by challenges in their coordination chemistry, especially for radiometal ions with large ionic radii. In this Account, we describe our efforts to develop chelation strategies for therapeutically relevant α-emitting radiometals, including ²²⁵Ac, ²¹³Bi, ²¹²Pb, and ²²³Ra. A central obstacle in stabilizing these ions arises from their large size and low charge density, which render many established macrocyclic chelators suboptimal. We demonstrate how the 18-membered macrocyclic ligand macropa provides a platform for effective complexation of large radiometals under mild conditions, and how systematic structural modifications of this scaffold elucidate key structure–function relationships governing metal binding. In addition, we discuss the development of a complementary class of dual-size selective chelators capable of accommodating both large therapeutic α-emitters and smaller diagnostic radiometals, thereby enabling matched theranostic applications within a unified ligand framework. Collectively, this work illustrates how fundamental principles of coordination chemistry can guide the rational design of radiometal chelators required for the advancement of α-particle–based targeted internal radiotherapy.