Synthesis and characterization of DOTA-(amide)4 derivatives

Equilibrium and kinetic behavior of their lanthanide(III) complexes

Azhar Pasha, Gyula Tircsó, Eniko Tircsóné Benyó, Erno Brücher, A. Dean Sherry

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Abstract

Lanthanide complexes of tetraamide derivatives of DOTA are of interest today because of their application as chemical exchange saturation transfer (CEST) agents for magnetic resonance imaging (MRI). The protonation constants of some simple tetraamide derivatives of DOTA and the stability constants of the complexes formed with some endogenous metal ions, namely Mg2+, Ca2+, Cu2+, Zn2+, and lanthanide(III) ions, have been studied. These complexes were found to be considerably less stable than the corresponding [M(DOTA)]2- complexes, largely due to the lower basicity of the tetraamide ligands. The Mg2+ and Ca 2+ complexes are well described by formation of only ML species at equilibrium while the Zn2+ and Cu2+ complexes exhibit one and two additional deprotonation steps above a pH of around 6, respectively. The extra deprotonation that occurs at high pH for the [Zn{DOTA-(amide) 4}]2+ complexes has been assigned to an amide deprotonation by 1H NMR spectroscopy. The first deprotonation step for the Cu2+ complexes was traced to formation of the ternary hydroxo complexes ML(OH) (by UV/Vis spectrophotometry) while the second step corresponds to deprotonation of an amide group to form ML(OH)H-1-type complexes. The trends in the stability constants of the [Ln{DOTA-(amide) 4}]3+ complexes follow similar trends with respect to ion size as those reported previously for the corresponding [Ln(DOTA)]- complexes, but again, the stability constants are about 10-11 orders of magnitude lower. A kinetic analysis of complex formation has shown that complexes are directly formed between a Ln3+ cation and fully deprotonated L without formation of a protonated intermediate. [Ln{DOTA-(MeAm)4}]3+ complex formation occurs at a rate that is two to three orders of magnitude slower than those of the corresponding [Ln(DOTA)]- complexes, while the variation in complex formation rates with Ln3+ ion size is opposite to that observed for the corresponding [Ln(DOTA)]- complexes. The Ce3+ and Eu 3+ complexes of DOTA-(MeAm)4 are kinetically inert with respect to acid-catalyzed dissociation, which suggests that these complexes may potentially be safe for use in vivo.

Original languageEnglish (US)
Pages (from-to)4340-4349
Number of pages10
JournalEuropean Journal of Inorganic Chemistry
Issue number27
DOIs
StatePublished - 2007

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Lanthanoid Series Elements
Deprotonation
Amides
Derivatives
Kinetics
Ions
Protonation
Spectrophotometry
Magnetic resonance
Alkalinity
Nuclear magnetic resonance spectroscopy
Metal ions
Cations
Ligands
Imaging techniques
Acids

Keywords

  • Contrast agents
  • Kinetics
  • Magnetic resonance imaging
  • Protonation constants
  • Stability constants

ASJC Scopus subject areas

  • Inorganic Chemistry

Cite this

Synthesis and characterization of DOTA-(amide)4 derivatives : Equilibrium and kinetic behavior of their lanthanide(III) complexes. / Pasha, Azhar; Tircsó, Gyula; Benyó, Eniko Tircsóné; Brücher, Erno; Sherry, A. Dean.

In: European Journal of Inorganic Chemistry, No. 27, 2007, p. 4340-4349.

Research output: Contribution to journalArticle

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abstract = "Lanthanide complexes of tetraamide derivatives of DOTA are of interest today because of their application as chemical exchange saturation transfer (CEST) agents for magnetic resonance imaging (MRI). The protonation constants of some simple tetraamide derivatives of DOTA and the stability constants of the complexes formed with some endogenous metal ions, namely Mg2+, Ca2+, Cu2+, Zn2+, and lanthanide(III) ions, have been studied. These complexes were found to be considerably less stable than the corresponding [M(DOTA)]2- complexes, largely due to the lower basicity of the tetraamide ligands. The Mg2+ and Ca 2+ complexes are well described by formation of only ML species at equilibrium while the Zn2+ and Cu2+ complexes exhibit one and two additional deprotonation steps above a pH of around 6, respectively. The extra deprotonation that occurs at high pH for the [Zn{DOTA-(amide) 4}]2+ complexes has been assigned to an amide deprotonation by 1H NMR spectroscopy. The first deprotonation step for the Cu2+ complexes was traced to formation of the ternary hydroxo complexes ML(OH) (by UV/Vis spectrophotometry) while the second step corresponds to deprotonation of an amide group to form ML(OH)H-1-type complexes. The trends in the stability constants of the [Ln{DOTA-(amide) 4}]3+ complexes follow similar trends with respect to ion size as those reported previously for the corresponding [Ln(DOTA)]- complexes, but again, the stability constants are about 10-11 orders of magnitude lower. A kinetic analysis of complex formation has shown that complexes are directly formed between a Ln3+ cation and fully deprotonated L without formation of a protonated intermediate. [Ln{DOTA-(MeAm)4}]3+ complex formation occurs at a rate that is two to three orders of magnitude slower than those of the corresponding [Ln(DOTA)]- complexes, while the variation in complex formation rates with Ln3+ ion size is opposite to that observed for the corresponding [Ln(DOTA)]- complexes. The Ce3+ and Eu 3+ complexes of DOTA-(MeAm)4 are kinetically inert with respect to acid-catalyzed dissociation, which suggests that these complexes may potentially be safe for use in vivo.",
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T1 - Synthesis and characterization of DOTA-(amide)4 derivatives

T2 - Equilibrium and kinetic behavior of their lanthanide(III) complexes

AU - Pasha, Azhar

AU - Tircsó, Gyula

AU - Benyó, Eniko Tircsóné

AU - Brücher, Erno

AU - Sherry, A. Dean

PY - 2007

Y1 - 2007

N2 - Lanthanide complexes of tetraamide derivatives of DOTA are of interest today because of their application as chemical exchange saturation transfer (CEST) agents for magnetic resonance imaging (MRI). The protonation constants of some simple tetraamide derivatives of DOTA and the stability constants of the complexes formed with some endogenous metal ions, namely Mg2+, Ca2+, Cu2+, Zn2+, and lanthanide(III) ions, have been studied. These complexes were found to be considerably less stable than the corresponding [M(DOTA)]2- complexes, largely due to the lower basicity of the tetraamide ligands. The Mg2+ and Ca 2+ complexes are well described by formation of only ML species at equilibrium while the Zn2+ and Cu2+ complexes exhibit one and two additional deprotonation steps above a pH of around 6, respectively. The extra deprotonation that occurs at high pH for the [Zn{DOTA-(amide) 4}]2+ complexes has been assigned to an amide deprotonation by 1H NMR spectroscopy. The first deprotonation step for the Cu2+ complexes was traced to formation of the ternary hydroxo complexes ML(OH) (by UV/Vis spectrophotometry) while the second step corresponds to deprotonation of an amide group to form ML(OH)H-1-type complexes. The trends in the stability constants of the [Ln{DOTA-(amide) 4}]3+ complexes follow similar trends with respect to ion size as those reported previously for the corresponding [Ln(DOTA)]- complexes, but again, the stability constants are about 10-11 orders of magnitude lower. A kinetic analysis of complex formation has shown that complexes are directly formed between a Ln3+ cation and fully deprotonated L without formation of a protonated intermediate. [Ln{DOTA-(MeAm)4}]3+ complex formation occurs at a rate that is two to three orders of magnitude slower than those of the corresponding [Ln(DOTA)]- complexes, while the variation in complex formation rates with Ln3+ ion size is opposite to that observed for the corresponding [Ln(DOTA)]- complexes. The Ce3+ and Eu 3+ complexes of DOTA-(MeAm)4 are kinetically inert with respect to acid-catalyzed dissociation, which suggests that these complexes may potentially be safe for use in vivo.

AB - Lanthanide complexes of tetraamide derivatives of DOTA are of interest today because of their application as chemical exchange saturation transfer (CEST) agents for magnetic resonance imaging (MRI). The protonation constants of some simple tetraamide derivatives of DOTA and the stability constants of the complexes formed with some endogenous metal ions, namely Mg2+, Ca2+, Cu2+, Zn2+, and lanthanide(III) ions, have been studied. These complexes were found to be considerably less stable than the corresponding [M(DOTA)]2- complexes, largely due to the lower basicity of the tetraamide ligands. The Mg2+ and Ca 2+ complexes are well described by formation of only ML species at equilibrium while the Zn2+ and Cu2+ complexes exhibit one and two additional deprotonation steps above a pH of around 6, respectively. The extra deprotonation that occurs at high pH for the [Zn{DOTA-(amide) 4}]2+ complexes has been assigned to an amide deprotonation by 1H NMR spectroscopy. The first deprotonation step for the Cu2+ complexes was traced to formation of the ternary hydroxo complexes ML(OH) (by UV/Vis spectrophotometry) while the second step corresponds to deprotonation of an amide group to form ML(OH)H-1-type complexes. The trends in the stability constants of the [Ln{DOTA-(amide) 4}]3+ complexes follow similar trends with respect to ion size as those reported previously for the corresponding [Ln(DOTA)]- complexes, but again, the stability constants are about 10-11 orders of magnitude lower. A kinetic analysis of complex formation has shown that complexes are directly formed between a Ln3+ cation and fully deprotonated L without formation of a protonated intermediate. [Ln{DOTA-(MeAm)4}]3+ complex formation occurs at a rate that is two to three orders of magnitude slower than those of the corresponding [Ln(DOTA)]- complexes, while the variation in complex formation rates with Ln3+ ion size is opposite to that observed for the corresponding [Ln(DOTA)]- complexes. The Ce3+ and Eu 3+ complexes of DOTA-(MeAm)4 are kinetically inert with respect to acid-catalyzed dissociation, which suggests that these complexes may potentially be safe for use in vivo.

KW - Contrast agents

KW - Kinetics

KW - Magnetic resonance imaging

KW - Protonation constants

KW - Stability constants

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