Modulation of the Lifetime of Water Bound to Lanthanide Metal Ions in Complexes with Ligands Derived from 1,4,7,10-Tetraazacyclododecane Tetraacetate (DOTA)

A series of di- and tetraamide derivatives of DOTA were synthesized, and their lanthanide(III) complexes were examined by multinuclear 1H-, 13C-, and 17O-NMR spectroscopy, and compared with literature data of similar, known complexes (Table). All ligands formed structures similar to the parent [LnIII(DOTA)]− complexes, with four N-atoms and four O-atoms from DOTA and one O-atom from the inner-sphere water molecules. Interestingly, the lifetimes τM of the inner-sphere, metal-bound water molecules vary widely, ranging from nano- to milliseconds, depending on the identity of the pendent amide side chains. In general, positively charged [LnIII(DOTA-tetraamide)]3+ complexes display the longest residence times (high τM values), while complexes with additional charged functional groups on the extended amides display much smaller τM values, even when the side groups are not directly coordinated to the central Ln3+ ions. The design of novel [LnIII(DOTA-tetraamide)]3+ complexes with a wide, tunable range of τM values is of prime importance for the application of fast-responding, paramagnetic chemical-exchange-saturation-transfer (PARACEST) imaging agents used for the study of physiological and metabolic processes.