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 [Ln^III(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 τ_M 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 [Ln^III(DOTA-tetraamide)]³⁺ complexes display the longest residence times (high τ_M values), while complexes with additional charged functional groups on the extended amides display much smaller τ_M values, even when the side groups are not directly coordinated to the central Ln³⁺ ions. The design of novel [Ln^III(DOTA-tetraamide)]³⁺ complexes with a wide, tunable range of τ_M 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.