Density Functional Theory Study on the Complexation of NOTA as a Bifunctional Chelator with Radiometal Ions

1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) is a key bifunctional chelator utilized for the complexation of metal ions in radiopharmaceutical applications; the ability of these chelators depends on the strength of their binding with ions. The focus of the present work is to evaluate the complexation of Cu²⁺, Ga³⁺, Sc³⁺, and In³⁺ radiometal ions with NOTA using density functional theory (B3LYP functional) and 6-311+G(2d,2p)/DGDZVP basis sets. The significant role of ion-water interactions in the chelation interaction energies in solution reflects the competition between ion-water and NOTA-ion interaction in the chelation process. There is reasonable agreement between experimental and theoretical binding constants, geometries, and ¹H NMR chemical shifts. Chelation interaction energies, Gibbs free energies, and entropies in solution show that the NOTA-Ga³⁺ and NOTA-Cu²⁺ are the most and least stable complexes, respectively. The natural atomic charges and second order perturbation analysis reveal charge transfer between NOTA and radiometal ions. The theoretical ¹H NMR chemical shifts of NOTA are in good agreement with experiment; these values are influenced by the presence of the ions, which have a deshielding effect on the protons of NOTA. Global scalar properties such as E_HOMO/E_LUMO, ΔE_LUMO-HOMO, and chemical hardness/softness confirm that the NOTA-Cu²⁺ complex, which has a singly occupied molecular orbital, has the lowest ΔE_LUMO-HOMO value, the least chemical hardness, and the highest chemical softness. The significant variation of the hardness and ΔE_LUMO-HOMO values of the complexes can be attributed to the different positions of the metal ions on the periodic table. This study affirms that, among the radiometal ions, Ga³⁺ can be used to effectively radiolabel NOTA chelator for radiopharmaceutical usage as it binds most stably with NOTA.