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

Abstract

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.

Molecular Dynamics Simulations of MRI-Relevant GdIII Chelates: Direct Access to Outer-Sphere Relaxivity

“…In the following calculations we used the approach and parameters of Powell et al, [27] where simplified expressions provide an adequate description of the electron relaxation [Eqs. (12) and (13)] and spin rotation [Eq. (14)] contributions to the 1 H and 17 O nuclear magnetic relaxation of these complexes.…”

Nuclear Spin Relaxation Parameters of MRI Contrast Agents – Insight from Quantum Mechanical Calculations

“…Fossheim et al studied, already in 1991, the structure-stability relationships of gadolinium(III) ion complexes by molecular mechanics (MM) calculations and molecular dynamics (MD) simulations. [16] Determination of water coordination numbers (q) by MM investigations have allowed to predict relaxivities on the basis of correlations to literature values. [17] Studies of conformational equilibria of gadolinium polyaminocarboxylate complexes have been appearing since the end of the nineties.…”

Solid‐Phase Synthesis of a Cyclic NGR‐Functionalized GdIIIDTPA Complex

“…[17] When designing synthetic approaches to stable Gd III DTPA complexes, it is important that all five carboxylic acids remain available for Gd III complexation in order to reduce toxity both in vitro and in vivo. [18][19][20] Alternative DTPA pentaester building blocks based on either glutamic acid (carboxylate terminated) or lysine (amine terminated) were reported by Williams et al [21] and Anelli et al [18] Recently, De Luca et al reported a solid-phase route to a DTPA-functionalized cholecystokinin octapeptide (CCK8) using the glutamic acid-based DTPA pentaester. [10] So far, the lysine-based DTPA analogue was not utilized for the solid-phase peptide synthesis.…”