Influence of Calcium-Induced Aggregation on the Sensitivity of Aminobis(methylenephosphonate)-Containing Potential MRI Contrast Agents

A novel class of 1,4,7,10-tetraazacyclododecane-1,4,7-tris(methylenecarboxylic) acid (DO3A)-based lanthanide complexes with relaxometric response to Ca2+ was synthesized, and their physicochemical properties were investigated. Four macrocyclic ligands containing an alkyl-aminobis(methylenephosphonate) side chain for Ca2+-chelation have been studied (alkyl is propyl, butyl, pentyl, and hexyl for L 1 , L 2 , L 3 , and L 4 , respectively). Upon addition of Ca2+, the r 1 relaxivity of their Gd3+ complexes decreased up to 61% of the initial value for the best compounds GdL 3 and GdL 4 . The relaxivity of the complexes was concentration dependent (it decreases with increasing concentration). Diffusion NMR studies on the Y3+ analogues evidenced the formation of agglomerates at higher concentrations; the aggregation becomes even more important in the presence of Ca2+. 31P NMR experiments on EuL 1 and EuL 4 indicated the coordination of a phosphonate to the Ln3+ for the ligand with a propyl chain, while phosphonate coordination was not observed for the analogue bearing a hexyl linker. Potentiometric titrations yielded protonation constants of the Gd3+ complexes. log K H1 values for all complexes lie between 6.12 and 7.11 whereas log K H2 values are between 4.61 and 5.87. Luminescence emission spectra recorded on the Eu3+ complexes confirmed the coordination of a phosphonate group to the Ln3+ center in EuL 1 . Luminescence lifetime measurements showed that Ca-induced agglomeration reduces the hydration number which is the main cause for the change in r 1. Variable temperature 17O NMR experiments evidenced high water exchange rates on GdL 1 , GdL 2 , and GdL 3 comparable to that of the aqua ion.