Comprehensive evaluation of the physicochemical properties of Ln(III) complexes of aminoethyl-DO3A as pH-responsive T(1) -MRI contrast agents

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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2933-2944
Number of pages12
JournalChemistry - A European Journal
Volume20
Issue number10
DOIs
Publication statusPublished - Mar 3 2014

Fingerprint

Magnetic resonance
Contrast Media
Amines
Metal ions
Magnetic Resonance Imaging
Imaging techniques
Alkalinity
Protons
Luminescence
Thermodynamic stability
Nitrogen
Metals
Ligands
Molecules
Kinetics
Acids
Water
Ions
Luminescent Measurements
Thermodynamics

Keywords

  • contrast agents
  • lanthanides
  • macrocyclic ligands
  • NMR spectroscopy
  • thermodynamics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Comprehensive evaluation of the physicochemical properties of Ln(III) complexes of aminoethyl-DO3A as pH-responsive T(1) -MRI contrast agents. / Baranyai, Z.; Rolla, Gabriele A.; Negri, Roberto; Forgács, Attila; Giovenzana, Giovanni B.; Tei, Lorenzo.

In: Chemistry - A European Journal, Vol. 20, No. 10, 03.03.2014, p. 2933-2944.

Research output: Contribution to journalArticle

Baranyai, Z. ; Rolla, Gabriele A. ; Negri, Roberto ; Forgács, Attila ; Giovenzana, Giovanni B. ; Tei, Lorenzo. / Comprehensive evaluation of the physicochemical properties of Ln(III) complexes of aminoethyl-DO3A as pH-responsive T(1) -MRI contrast agents. In: Chemistry - A European Journal. 2014 ; Vol. 20, No. 10. pp. 2933-2944.
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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.",
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AU - Forgács, Attila

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KW - contrast agents

KW - lanthanides

KW - macrocyclic ligands

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KW - thermodynamics

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