UK chemists reveal experimental evidence for a postulated intermediate in MRI contrast agent formation.

David Parker and colleagues at Durham University, UK, have isolated a compound that they say could represent an intermediate in the complexation of a macrocyclic amide ligand (Dotam) to gadolinium that has been put forward by chemists in the past. Such gadolinium complexes are extensively used as contrast agents in magnetic resonance imaging (MRI) to detect tumours. Understanding how the complexes form and dissociate is important because uncomplexed Gd(III) is toxic, so the contrast agent complex must be stable over its lifetime in the body.

Parker found that in this intermediate the gadolinium ion is bound to the carbonyl oxygens of the ligand and to four water molecules, while the macrocycle has a ring conformation similar to that of uncomplexed (H₂Dota)Cl₂. The researchers' analysis suggests that as the macrocyclic Dotam ligand is deprotonated and water molecules are displaced, the ligand can open out to let the gadolinium ion enter.

Jean Desreux at the University of Liège, Belgium, welcomed the work. 'It has often been assumed that the complexation of Gd(III) by Dota proceeds through the formation of an intermediate in which the metal ion is not yet fully encapsulated in the ligand,' said Desreux. 'This is the first experimental proof of the hypothesis.'

Angelo Amoroso at Cardiff University, UK, agreed that this is the best current model for what might occur when a metal first interacts with this type of ligand. 'It is a somewhat surprising result to actually get the crystal structure and see the four "floppy" arms chelating the metal, with the protonated macrocycle sitting below,' said Amoroso.
 
Parker believes his findings will 'stimulate further work designed to define the intimate details of metal association and dissociation pathways of relevance to the behaviour of these and related structures in their use as relaxation agents.'

Caroline Moore