Comprehensive Evaluation of the Physicochemical Properties of Ln super(III) Complexes of Aminoethyl-DO3A as pH-Responsive T sub(1)-MRI Contrast Agents

• Published in: Chemistry : a European journal Vol. 20; no. 10; pp. 2933 - 2944
• Main Authors: Baranyai, Zsolt, Rolla, Gabriele A, Negri, Roberto, gacs, Attila, Giovenzana, Giovanni B, Tei, Lorenzo
• Format: Journal Article
• Language: English
• Published: 01-03-2014
• Subjects: Amines; Contrast agents; Ligands; Luminescence; Magnetic resonance imaging; Stability; Switches
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201304063

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 super(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-methylaminoethy l-DO3A). The physicochemical properties of the Ln super(III) complexes were investigated for the evaluation of their potential applicability as magnetic resonance imaging (MRI) contrast agents. In particular, a super(1)H and super(17)ONMR relaxometric study was carried out for these Gd super(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 super(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 super(1)HNMR studies. Equilibria between differently hydrated species were found for most of the complexes at both acidic and basic pH. The thermodynamic stability of Ca super(II), Zn super(II), Cu super(II) and Ln super(III) complexes and kinetics of formation and dissociation reactions of Ln super(III) complexes of AE-DO3A and DMAE-DO3A were investigated showing stabilities comparable to currently approved Gd super(III)-based CAs. In detail, higher total basicity ( capital sigma logK sub(i) super( )H and higher stability constants of Ln super(III) complexes were found for AE-DO3A with respect to DMAE-DO3A (i.e., logK sub(Gd-AE-DO3A) =22.40 and logK sub(Gd-DMAE-DO3A)=20.56). The transmetallation reactions of Gd super(III) complexes are very slow (Gd-AE-DO3A: t sub(1/2)=2.710 super(4)h; Gd-DMAE-DO3A: 1.110 super(5)h at pH7.4 and 298K) and occur through proton-assisted dissociation. pH Switches: N-Substituted aminoethyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A)-based complexes were prepared to obtain pH-sensitive T sub(1)-MRI contrast agents. A detailed evaluation of the physicochemical properties of Ln super(III) complexes was undertaken by different techniques, highlighting the structural variations triggered by the protonation of the pendant amine and the effect of the substituents on the corresponding nitrogen atom (see figure).