Computer-Assisted Design of Macrocyclic Chelators for Actinium-225 Radiotherapeutics

Actinium-225 (²²⁵Ac) is an excellent candidate for targeted radiotherapeutic applications for treating cancer, because of its 10-day half-life and emission of four high-energy α²⁺ particles. To harness and direct the energetic potential of actinium, strongly binding chelators that remain stable in vivo during biological targeting must be developed. Unfortunately, controlling chelation for actinium remains challenging. Actinium is the largest +3 cation on the periodic table and has a 6d⁰5f⁰ electronic configuration, and its chemistry is relatively unexplored. Herein, we present theoretical work focused on improving the understanding of actinium bonding with macrocyclic chelating agents as a function of (1) macrocycle ring size, (2) the number and identity of metal binding functional groups, and (3) the length of the tether linking the metal binding functional group to the macrocyclic backbone. Actinium binding by these chelators is presented within the context of complexation with DOTA^4-, the most relevant Ac³⁺ binding agent for contemporary radiopharmaceutical applications. The results enabled us to develop a new strategy for actinium chelator design. The approach is rooted in our identification that Ac³⁺-chelation chemistry is dominated by ionic bonding interactions and relies on (1) maximizing electrostatic interactions between the metal binding functional group and the Ac³⁺ cation and (2) minimizing electronic repulsion between negatively charged actinium binding functional groups. This insight will provide a foundation for future innovation in developing the next generation of multifunctional actinium chelators.