Stabilities of Ac ³⁺ Complexes Relevant as Radiopharmaceuticals

We present a detailed density functional theory (DFT) investigation of the structural features and thermodynamic stabilities of La³⁺ and Ac³⁺ complexes relevant to develop radiopharmaceutical agents. A total of 16 chelators were considered, covering the acyclic and macrocyclic families functionalized with different numbers and types of donor atoms. The bond distances of the Ac³⁺ coordination environment are systematically longer than those obtained for the La³⁺ analogues, which allowed us to estimate an ionic radius for Ac³⁺ in coordination number 9 of 1.275 ± 0.020 Å (1.216 and 1.206 Å were proposed for La³⁺). Energy decomposition analysis (EDA) provided hints into the nature of the metal-ligand interactions and their relative weight in La³⁺ and Ac³⁺ complexes. A thermodynamic DFT study allowed us to estimate the stability constants of the Ac³⁺ complexes from those of the La³⁺ ones, as for the latter experimental values are available in the literature. These studies evidenced that Ac³⁺ tends to form complexes with lower thermodynamic stability in comparison with La³⁺, with the exception of one of the leading chelators for Ac³⁺, MACROPA²⁻, and the unexpected case of OCTAPA⁴⁻. Overall, the methodology reported here will allow identifying chelators well suited for Ac³⁺ coordination, thereby aiding the design of radiopharmaceuticals based on [²²⁵Ac]Ac³⁺ for targeted α therapy (TAT).