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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

Comprehensive Evaluation of the Physicochemical Properties of Ln(III) Complexes of aminoethyl-DO3A as pH-responsive T(1) -MRI Contrast Agents

Zsolt Baranyai, Gabriele A Rolla, Roberto Negri, Attila Forgács, Giovanni B Giovenzana, Lorenzo Tei

Chemistry. 2014 Mar 3;20(10):2933-44.

PMID: 24590497

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP100634911	Gadolinium(III) hydroxide hydrate		100634-91-1	Price

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