Matching a chelator (DOTA) with ions for radio-pharmaceutical applications using DFT study.

Abstract

Organometallic chelators can be potentially used for radiometal-based pharmaceuticals. The bifunctional chelator, which is covalently bound to a lead compound, forms a stable chelator―ion complex to deliver an isotope, as a labelling agent, towards a specific in vivo target. The quest to find the optimal match between chelators and radiometal ions is of interest in the field of radio pharmaceuticals. A loss of radiometal ion from a chelator without reaching to its specific target organ in vivo could be disastrous to the body. The present project is focused on the complexation of 1, 4, 7, 10-tetraazacyclododecane-1, 4, and 7, 10-tetraacetic acid (DOTA) with alkali metals and radiometal ions. Herein, we investigated DOTA―alkali metal ions complexes with density functional theory using B3LYP and ωB97XD functionals and the 6-311+G(2d,2p) basis set for Li+, Na+ and K+ and Def2-TZVPD for Rb+. Conformational possibilities, starting from x-ray crystal structures and considering a different number of arms (2, 3 and 4) interacting with the ions were explored. Interaction and relaxation energies, thermochemical parameters, HOMO/LUMO energies, ΔEHOMO-LUMO and chemical hardness indicate the decrease in the stability of DOTA―ions down the alkali metal series. Natural bond orbital analysis reveals charge transfer between DOTA and alkali metals. Regarding radiometal ions, the geometries for the various complexes were consistent with experimentally reported binding constants. NBO analysis indicates charge transfer from the chelator to the radio metals resulting in reduced positive atomic charge values for all the ions. DOTA―Ga3+, DOTA―In3+ and DOTA―Sc3+ complexes recorded higher ΔELUMO-HOMO energies and chemical hardness values. The DOTA―Cu2+ complex was the least stable among the selected complexes. This study serves as a guide to researchers in the field of organometallic chelators, particularly; radio-pharmaceuticals in finding the efficient optimal match between chelators and different metal ions.