Favorable Symmetric Structures of Radiopharmaceutically Important Neutral Cyclen-Based Ligands

Abstract

Cyclen-based ligands are prominent tools for transferring radioisotopes through the human body. A crucial criterion is the stability of their complexes, which is partly determined by the stabilization of the free ligand in solution. For the assessment of the later property, the favored conformation(s) in the solution must be known. In the present study, the conformational space of four neutral cyclen-based ligands was elucidated by a multi-step procedure: the survey of the conformational space using molecular mechanics (MM) was followed by Density Functional Theory (DFT) calculations on the low-energy conformers and evaluation of the solvent effects. The results revealed several low-energy conformers in aqueous solution. In terms of electronic energies, a significant preference of symmetric structures (C4 or C2—similar to the ligand arrangements in their metal complexes) was obtained. The thermal contributions to the Gibbs free energy (mainly the vibrational ones) tend to decrease this preference by several kJ/mol against non-symmetric structures. Nonetheless, the advantage of compact symmetric structures was confirmed in all the four studied cases.