title: Comprehensive evaluation of the physicochemical properties of Ln(III) complexes of aminoethyl-DO3A as pH-responsive T(1) -MRI contrast agents.
abstract: N-Substituted aminoethyl groups were attached to 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) with the aim to design pH-responsive Ln(III) complexes based on the pH-dependent on/off ligation of the amine nitrogen to the metal ion. The following ligands were synthesized: AE-DO3A (aminoethyl-DO3A), MAE-DO3A (N-methylaminoethyl-DO3A), DMAE-DO3A (N,N-dimethylaminoethyl-DO3A) and MEM-AE-DO3A (N-methoxyethyl-N-methylaminoethyl-DO3A). The physicochemical properties of the Ln(III) complexes were investigated for the evaluation of their potential applicability as magnetic resonance imaging (MRI) contrast agents. In particular, a (1) H and (17) O NMR relaxometric study was carried out for these Gd(III) complexes at two different pH values: at basic pH (pendant amino group coordinated to the metal centre) and at acidic pH (protonated amine, not interacting with the metal ion). Eu(III) complexes allow one to estimate the number of inner-sphere water molecules through luminescence lifetime measurements and obtain some structural information through variable-temperature (VT) high-resolution (1) H NMR studies. Equilibria between differently hydrated species were found for most of the complexes at both acidic and basic pH. The thermodynamic stability of Ca(II) , Zn(II) , Cu(II) and Ln(III) complexes and kinetics of formation and dissociation reactions of Ln(III) complexes of AE-DO3A and DMAE-DO3A were investigated showing stabilities comparable to currently approved Gd(III) -based CAs. In detail, higher total basicity (Σlog Ki (H) ) and higher stability constants of Ln(III) complexes were found for AE-DO3A with respect to DMAE-DO3A (i.e., log KGd-AE-DO3A =22.40 and log KGd-DMAE-DO3A =20.56). The transmetallation reactions of Gd(III) complexes are very slow (Gd-AE-DO3A: t1/2 =2.7×10(4)  h; Gd-DMAE-DO3A: 1.1×10(5)  h at pH 7.4 and 298 K) and occur through proton-assisted dissociation.
authors.affiliation: Department of Inorganic and Analytical Chemistry, University of Debrecen, H-4010 Debrecen Egyetem tér 1 (Hungary).
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Baranyai
authors.forename: Gabriele A
authors.initials: GA
authors.lastname: Rolla
authors.forename: Roberto
authors.initials: R
authors.lastname: Negri
authors.forename: Attila
authors.initials: A
authors.lastname: Forgács
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Giovenzana
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Tei
mesh_terms: D003287:Contrast Media / Q000737:chemistry*; D005682:Gadolinium / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D028581:Lanthanoid Series Elements / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D011522:Protons; D013816:Thermodynamics; D014867:Water
chemical_list: C520644:1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid; D003287:Contrast Media; D006573:Heterocyclic Compounds, 1-Ring; D028581:Lanthanoid Series Elements; D011522:Protons; D014867:Water; D005682:Gadolinium
keywords: NMR spectroscopy; contrast agents; lanthanides; macrocyclic ligands; thermodynamics