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Comprehensive Evaluation of the Physicochemical Properties of Ln III Complexes of Aminoethyl‐DO3A as pH‐Responsive T 1 ‐MRI Contrast Agents
Author(s) -
Baranyai Zsolt,
Rolla Gabriele A.,
Negri Roberto,
Forgács Attila,
Giovenzana Giovanni B.,
Tei Lorenzo
Publication year - 2014
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201304063
Subject(s) - chemistry , protonation , amine gas treating , dota , metal , molecule , chemical stability , dissociation (chemistry) , coordination sphere , crystallography , ion , inorganic chemistry , stereochemistry , chelation , organic chemistry
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 K i H ) and higher stability constants of Ln III complexes were found for AE ‐ DO3A with respect to DMAE ‐ DO3A (i.e., log K Gd‐ AE‐DO3A =22.40 and log K Gd‐ DMAE‐DO3A =20.56). The transmetallation reactions of Gd III complexes are very slow (Gd‐ AE ‐ DO3A : t 1/2 =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.