Structure-stability relationships of Gd(III) ion complexes for magnetic resonance imaging

Molecular mechanical calculations and molecular dynamics simulations, based on the AMBER force field, were used to examine the molecular structures and stabilities of nine multidentate ligands and their Gd(III) ion complexes. The magnitude of various factors determining the stability of multidentate Gd(III) complexes, including the energy loss due to change of ligand conformation by complexation, the energy gain from cation-ligand attraction, and effects of intramolecular hydrogen bonding, were calculated by molecular mechanics. The fit between the Gd cation and the binding cavity in the ligands was examined by molecular graphics techniques. Intramolecular hydrogen bonds in free ligands with amide or hydroxyl as H-bond donors usually disfavor complex formation, due to disruption of hydrogen bonds during complex formation. Intramolecular hydrogen bonds may contribute to enhance complex stability if they make the desolvation energy of the free ligands smaller. The calculated complex stabilities were in reasonable agreement with experimental log K values which were available for five of the compounds. The calculated complex stabilities of two hitherto unsynthesized covalently constrained DTPA-derivatives and a DOTA-derivative bearing phenoxy groups as pendant arms indicate that these may form Gd(III) complexes with sufficient stability for use in magnetic resonance imaging techniques.