DFT calculation of Ac3+ and Bi3+ complexation with hybrid chelator 3p-C-DEPA for targeted alpha therapy

Abstract

Abstract The stability constant (logK 1 ) and reactivity are ultimately the most crucial components to consider during the evaluation and selection of chelators to match with a specific radiometal ion for usage in radiopharmaceutical applications. These components evaluate the thermodynamic stability of the radiometal-chelator complex. Additionally, the effectiveness of chelator in binding with radiometal ions with relatively large atomic radii (e.g., 213 Bi 3+ and 225 Ac 3+ ) coupled with charge-diffuse properties result in weaker metal-ligand interactions, and this poses challenges in chelator development. The (2-[(carboxymethyl)]5-(4-nitrophenyl-1-[4,7,10-tris(carboxymethyl)-1,4,7,10-tPentan-2-yl) amino] acetic acid (3p- C -DEPA) is a new hybrid chelator designed for potential radio-complexation applications in radio-theranostics and preclinical data has shown great promise for this chelating ligand. Hence, this study investigates the stability constant and chemical reactivity descriptors of the complex generated between 3p- C -DEPA and the α-emitting radioisotopes 213 Bi 3+ and 225 Ac 3+ as well as the β-emitting particle 177 Lu 3+ for the first-time using density functional theory (DFT) calculations. The method employs two functional densities, MO6-HF and B3LYP, using the basis set 6-311G(d)/SDD, alongside the continuous solvation models SMD (solvation model density) and COSMO (conductor-like screening model). The interactions of all radiometals with the hybrid chelator 3p- C -DEPA are compared to the benchmark chelator, 1,4,7,10-tetrazacyclodecane-1,4,7,10-tetraacetic acid (DOTA), yielding comprehensive data on the stability constants and based structural features of radiometal-chelator complexes. DFT analysis has shown that the stability of the 3p- C -DEPA chelator complex formation is influenced by the atomic radius of the radiometal and the number of nitrogen and oxygen donors, proving to be effective for Ac 3+ and Bi 3+ , in contrast to Lu 3+ , which shows lower stability constant values.