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 EHOMO/ELUMO, ΔELUMO-HOMO, and chemical hardness/softness confirm that the NOTA-Cu2+ complex, which has a singly occupied molecular orbital, has the lowest ΔELUMO-HOMO value, the least chemical hardness, and the highest chemical softness. The significant variation of the hardness and ΔELUMO-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.