New Insights for Pursuing High Relaxivity MRI Agents from Modelling the Binding Interaction of GdIII Chelates to HSA (original) (raw)

It was recognized early on that the relaxivity of a Gd III complex at 0.5-1 T can be strongly enhanced if its molecular correlation time is lengthened by linking it to a slowly moving macromolecule. In this context, a huge amount of attention has been devoted in the past decade to the study of systems able to form noncovalent adducts with serum albumin, which also has the advantage of yielding systems that remain confined in the blood vessels. Theory foresees the attainment of relaxivities > 100 mm À1 s À1 for macromolecular monoaquo Gd chelates characterized by a molecular reorientation time of 10-30 ns. However, in spite of a number of investigated systems, relaxivities of such magnitude for Gd chelates bound to HSA have never been found. One major limiting factor has been recognized to be the occurrence of an insufficiently fast exchange rate of the coordinated water (t M ). Therefore a primary requisite for pursuing high relaxivity for a Gd-L/HSA adduct is the occurrence of a relatively fast exchange of the inner-sphere water molecule, that is, t M has to be in the range of tens of nanoseconds at room temperature. Within macrocyclic systems, Gd-DOTMA ((1R,4R,7R,10R)-a,a',a'',a'''-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,1,10-tetraacetic acid satisfies this condition (t M = 68 ns). On this basis, we synthesised two Gd-DOTMA-like complexes with the expectation that they would show high binding affinity to HSA, faster exchange of the coordinated water and overall rigidity of the coordination cage, a property that has been associated with a long electronic relaxation time and is a further requisite for the attainment of very high relaxivity.