GdIII complexes of dota-derived N-sulfonylacetamides (H-4(dota-NHSO2R)=10-{2-[(R)sulfonylamino]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid): A new class of relaxation agents for magnetic resonance imaging applications

Four new ligands for lanthanide ions based on the H₃do3a (= 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) structure and bearing one N-sulfonylacetamide arm were synthesized, i.e., H₄dota-NHSO ₂R = 10-{2-[(R)sulfonylamino]-2-oxoethyl}-1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acids 1a-e. A ¹⁵N-NMR study of the ¹⁵N-labelled Eu³⁺ complex of one such ligands, 1d, showed that the coordination of the N-sulfonylacetamide arm involves the carbonyl O-atom rather than the N-atom. The relaxometric properties of the corresponding Gd³⁺ complexes were investigated as a function of pH and temperature. These complexes have relaxivities in the range 4.5-5.3 mM ^-1 s^-1, at 20 MHz and 25°, and are characterized by a single H₂O molecule in their inner coordination sphere. The mean residence lifetime of this molecule is relatively long (500-700 ns) compared to other anionic complexes. The slow rate of H₂O exchange can be justified by the extensive delocalization of the negative charge on the N-sulfonylacetamide arm. The long residence time of the coordinated H ₂O allowed the observation of the effect of the prototropic exchange on the relaxivity. The study of the interaction between the complex [Gd(1e)]- and HSA revealed a weak affinity constant highlighting the importance of a localized negative charge on the complex to promote a strong interaction with the protein.