title: Paramagnetic lanthanide(III) complexes as pH-sensitive chemical exchange saturation transfer (CEST) contrast agents for MRI applications.
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.
authors.affiliation: Dipartimento di Chimica I.F.M., Università degli Studi di Torino, Torino, Italy. aime@ch.unito.it
authors.forename: Silvio
authors.initials: S
authors.lastname: Aime
authors.forename: Alessandro
authors.initials: A
authors.lastname: Barge
authors.forename: Daniela
authors.initials: D
authors.lastname: Delli Castelli
authors.forename: Franco
authors.initials: F
authors.lastname: Fedeli
authors.forename: Armando
authors.initials: A
authors.lastname: Mortillaro
authors.forename: Flemming U
authors.initials: FU
authors.lastname: Nielsen
authors.forename: Enzo
authors.initials: E
authors.lastname: Terreno
mesh_terms: D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry; D003287:Contrast Media / Q000737:chemistry; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D028581:Lanthanoid Series Elements; D008024:Ligands; D008279:Magnetic Resonance Imaging; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D002614:Chelating Agents; D003287:Contrast Media; D006573:Heterocyclic Compounds, 1-Ring; D028581:Lanthanoid Series Elements; D008024:Ligands; D009942:Organometallic Compounds; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D005998:Glycine