Chiral gadolinium complexes as potential contrast agents
The long electronic relaxation time and the high paramagnetism of the gadolinium(III) ion makes it ideal for use as a contrast agent in Magnetic Resonance Imaging. As a result of its toxicity, gadolinium must be administered in the form of a kinetically inert complex. By coupling a gadolinium(III) chelate to a macromolecule, substantial gains in relaxivity (the efficacy of a contrast agent) may be obtained. To this end the synthesis of three types of ligand, substituted with amino- or carboxylate bearing groups, was undertaken. A derivative of 1,4,7,10-tetraazacyclododecane with three amino bearing chains substituted at carbon was synthesised as a single enantiomer. An effective route to acetate substituted derivatives of D03A was developed. The lanthanide complexes of these ligands do not exhibit the expected properties of a q = 2 complex, and therefore do not represent useful chelates for application in a slowly tumbling system. A study of the lanthanide(in) complexes of all four stereoisomers of tetra(carboxyethyl) DOTA derivatives has been performed. The rate of water exchange has been found to be dependent upon the proportion of a complex adopting a twisted square antiprism in solution. This is ascribed to the steric crowding of the water binding site in this isomer. 2-D EXSY NMR experiments show that the [Ln.(RRRR-)] and [Ln.(RKRS-)] isomers do not undergo rapid arm rotation at room temperature, showing that ring motion is decoupled from arm rotation. This rigidity increases the stability of these complexes with respect to metal ion dissociation. A selective synthesis of the [Ln.(RRRR-)] diastereoisomeric complex is described. Crystal structures of the [Eu.(RRRR-)], [Gd.(RRRR-)] and [Tb.(RRRR-)] complexes each reveal a monocapped square antiprismatic co-ordination geometry at the metal centre in which there is one bound water molecule.