Favorable Symmetric Structures of Radiopharmaceutically Important Anionic (2-) Cyclen-Based Ligands

Cyclen-based ligands are among the most preferred ones in radiopharmacy, where they are mainly applied for transferring radioisotopes through the human body. A crucial criterion is the stability of their metal–ligand complexes, which depends on the stabilization of the free ligand in solution. However, these flexible ligands can have numerous conformations, and for a reliable evaluation of the dissociation energy, the most stable one(s) in solution must be known. In the present study, the low-energy conformational space of four anionic (2-) cyclen-based ligands has been elucidated in aqueous solution by a joint molecular mechanics (MM)/Density Functional Theory (DFT) procedure. The results revealed a significant preference for C2 symmetric structures, more or less resembling the arrangements in their metal complexes. The computed dissociation energies agree with the experimentally found stability trend for the Pb2+ complexes with ligands containing picolinate pendant arms. For complexes with mixed donor groups (carboxyl, amide, pyridine), significant thermodynamic stabilities were predicted.