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 225AcAc3+ for targeted α therapy (TAT).