Paramagnetic Lanthanide(III) complexes as pH‐sensitive chemical exchange saturation transfer (CEST) contrast agents for MRI applications

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Abstract
The recently introduced new class of contrast agents (CAs) based on chemical exchange saturation transfer (CEST) may have a huge potential for the development of novel applications in the field of MRI. In this work we explored the CEST properties of a series of Lanthanide(III) complexes (Ln = Eu, Dy, Ho, Er, Tm, Yb) with the macrocyclic DOTAM‐Gly ligand, which is the tetraglycineamide derivative of DOTA (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid). These complexes possess two pools of exchangeable protons represented by the coordinated water and the amide protons. Yb‐DOTAM‐Gly displays the most interesting CEST properties when its amide N‐H resonance (16 ppm upfield H2O signal) is irradiated. Up to 70% suppression of the water signal is obtained at pH 8. As the exchange rate of amide protons is base‐catalyzed, Yb‐DOTAM‐Gly results to be an efficient pH‐responsive probe in the 5.5–8.1 pH range. Moreover, a ratiometric method has been set up in order to remove the dependence of the observed pH responsiveness from the absolute concentration of the paramagnetic agent. In fact, the use of a mixture of Eu‐DOTAM‐Gly and Yb‐DOTAM‐Gly, whose exchangeable proton pools are represented by the coordinated water (ca. 40 ppm downfield H2O signal at 312K) and amide protons, respectively, produces a pH‐dependent CEST effect which is the function of the concentration ratio of the two complexes. Magn Reson Med 47:639–648, 2002.

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