Comprehensive Evaluation of the Physicochemical Properties of LnIII Complexes of Aminoethyl‐DO3A as pH‐Responsive T1‐MRI Contrast Agents1. Issue 10 (7th February 2014)

• Record Type: Journal Article
• Authors: Baranyai, Zsolt; Rolla, Gabriele A.; Negri, Roberto; Forgács, Attila; Giovenzana, Giovanni B.; Tei, Lorenzo
• Is Part Of: Chemistry. Volume 20:Issue 10(2014)
• Page Start: 2933
• Page End: 2944
• Publication Date: 2014-02-07
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201304063
• Languages: English
• ISSNs: 0947-6539

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p> <italic>N</italic>‐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<sup>III</sup> complexes based on the pH‐dependent on/off ligation of the amine nitrogen to the metal ion. The following ligands were synthesized: <bold>AE</bold>‐<bold>DO3A</bold> (aminoethyl‐DO3A), <bold>MAE</bold>‐<bold>DO3A</bold> (<italic>N</italic>‐methylaminoethyl‐DO3A), <bold>DMAE</bold>‐<bold>DO3A</bold> (<italic>N</italic>, <italic>N</italic>‐dimethylaminoethyl‐DO3A) and <bold>MEM</bold>‐<bold>AE</bold>‐<bold>DO3A</bold> (<italic>N</italic>‐methoxyethyl‐<italic>N</italic>‐methylaminoethyl‐DO3A). The physicochemical properties of the Ln<sup>III</sup> complexes were investigated for the evaluation of their potential applicability as magnetic resonance imaging (MRI) contrast agents. In particular, a <sup>1</sup>H and <sup>17</sup>O NMR relaxometric study was carried out for these Gd<sup>III</sup> 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<sup>III</sup> 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 <sup>1</sup>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<sup>II</sup>, Zn<sup>II</sup>, Cu<sup>II</sup> and Ln<sup>III</sup> complexes and kinetics of formation and dissociation reactions of Ln<sup>III</sup> complexes of <bold>AE</bold>‐<bold>DO3A</bold> and <bold>DMAE</bold>‐<bold>DO3A</bold> were investigated showing stabilities comparable to currently approved Gd<sup>III</sup>‐based CAs. In detail, higher total basicity (Σlog <italic>K<sub>i</sub></italic><sup>H</sup>) and higher stability constants of Ln<sup>III</sup> complexes were found for <bold>AE</bold>‐<bold>DO3A</bold> with respect to <bold>DMAE</bold>‐<bold>DO3A</bold> (i.e., log <italic>K</italic><sub>Gd‐<bold>AE‐DO3A</bold></sub>=22.40 and log <italic>K</italic><sub>Gd‐<bold>DMAE‐DO3A</bold></sub>=20.56). The transmetallation reactions of Gd<sup>III</sup> complexes are very slow (Gd‐<bold>AE</bold>‐<bold>DO3A</bold>: <italic>t</italic><sub>1/2</sub>=2.7×10<sup>4</sup> h; Gd‐<bold>DMAE</bold>‐<bold>DO3A</bold>: 1.1×10<sup>5</sup> h at pH 7.4 and 298 K) and occur through proton‐assisted dissociation.</p> </abstract>