H5dotasa (=(αRS)-α-(carboxymethyl)-1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid), an asymmetrical derivative of H4dota (=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) substituted at one acetate pendant arm

1H-NMR and potentiometric studies of the ligand and its lanthanide(III) complexes

João P. André, E. Brücher, R. Király, Rui A. Carvalho, Helmut Mäcke, Carlos F G C Geraldes

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Abstract

The ligand H5dotasa (=(αRS)-α-(carboxymethyl)-1,4,7, 10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) is a H4dota-like macrocyclic ligand with a carboxymethyl CH2COOH substituent at the C(α) atom of one of the four acetate pendant arms of H4dota (=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), present as a racemic mixture of (αR) and (αS) enantiomers. The protonation constants of the ligand were determined by potentiometry, giving values close to those of H4dota except for the extra pK3 value of 5.35 assigned to protonation of the extra carboxylate group in the α-substituted (=succinic acid) pendant arm. The 1H-NMR spectra of H5dotasa at different pH values are too complex to allow the determination of its microscopic protonation scheme, due to the presence of multiple isomeric structures in solution. The thermodynamic stability constant of its Gd3+ chelate was determined by a potentiometric method, and the value obtained, log KML = 27.2 (0.2), is higher than for the [Gd(dota)(OH2)]- complex. The solution structure of the asymmetric Ln3+ chelates of dotasa was studied by 1H-NMR spectroscopy, indicating the presence of four isomers, corresponding to the combination of the antiprismatic (M) and twisted antiprismatic (M) helicities of the pendant arms and to the (αR) and (αS) configurations at the substituted pendant arm. The m/M isomer ratio decreases along the lanthanide series, with the m isomer decreasing from 90% at La to ca. 50% from Eu-Lu. This shows that the expected m isomer population of the [Gd(dotasa)(OH 2)]2- complex is higher than for the unsubstituted [Gd(dota)(OH2)]- (ca. 15%) but lower than for a Gd 3+ chelate of an α,α′,α″, α‴-tetrasubstituted (RRRR)-configurated dota (ca. 70%). Thus the stabilization of the m isomer by C monosubstitution at the dota acetate pendant arm in [Gd(dotasa)(OH2)]2- is responsible for its increased H2O-exchange rate and higher relaxivity.

Original languageEnglish
Pages (from-to)633-646
Number of pages14
JournalHelvetica Chimica Acta
Volume88
Issue number3
DOIs
Publication statusPublished - 2005

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Lanthanoid Series Elements
Rare earth elements
Isomers
acetates
Acetates
isomers
Ligands
Nuclear magnetic resonance
Protonation
Derivatives
nuclear magnetic resonance
ligands
acids
chelates
Acids
Potentiometry
Succinic Acid
Thermodynamics
Magnetic Resonance Spectroscopy
potentiometric analysis

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

@article{a387b999b6d048488696d72399979637,
title = "H5dotasa (=(αRS)-α-(carboxymethyl)-1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid), an asymmetrical derivative of H4dota (=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) substituted at one acetate pendant arm: 1H-NMR and potentiometric studies of the ligand and its lanthanide(III) complexes",
abstract = "The ligand H5dotasa (=(αRS)-α-(carboxymethyl)-1,4,7, 10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) is a H4dota-like macrocyclic ligand with a carboxymethyl CH2COOH substituent at the C(α) atom of one of the four acetate pendant arms of H4dota (=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), present as a racemic mixture of (αR) and (αS) enantiomers. The protonation constants of the ligand were determined by potentiometry, giving values close to those of H4dota except for the extra pK3 value of 5.35 assigned to protonation of the extra carboxylate group in the α-substituted (=succinic acid) pendant arm. The 1H-NMR spectra of H5dotasa at different pH values are too complex to allow the determination of its microscopic protonation scheme, due to the presence of multiple isomeric structures in solution. The thermodynamic stability constant of its Gd3+ chelate was determined by a potentiometric method, and the value obtained, log KML = 27.2 (0.2), is higher than for the [Gd(dota)(OH2)]- complex. The solution structure of the asymmetric Ln3+ chelates of dotasa was studied by 1H-NMR spectroscopy, indicating the presence of four isomers, corresponding to the combination of the antiprismatic (M) and twisted antiprismatic (M) helicities of the pendant arms and to the (αR) and (αS) configurations at the substituted pendant arm. The m/M isomer ratio decreases along the lanthanide series, with the m isomer decreasing from 90{\%} at La to ca. 50{\%} from Eu-Lu. This shows that the expected m isomer population of the [Gd(dotasa)(OH 2)]2- complex is higher than for the unsubstituted [Gd(dota)(OH2)]- (ca. 15{\%}) but lower than for a Gd 3+ chelate of an α,α′,α″, α‴-tetrasubstituted (RRRR)-configurated dota (ca. 70{\%}). Thus the stabilization of the m isomer by C monosubstitution at the dota acetate pendant arm in [Gd(dotasa)(OH2)]2- is responsible for its increased H2O-exchange rate and higher relaxivity.",
author = "Andr{\'e}, {Jo{\~a}o P.} and E. Br{\"u}cher and R. Kir{\'a}ly and Carvalho, {Rui A.} and Helmut M{\"a}cke and Geraldes, {Carlos F G C}",
year = "2005",
doi = "10.1002/hlca.200590044",
language = "English",
volume = "88",
pages = "633--646",
journal = "Helvetica Chimica Acta",
issn = "0018-019X",
publisher = "Verlag Helvetica Chimica Acta AG",
number = "3",

}

TY - JOUR

T1 - H5dotasa (=(αRS)-α-(carboxymethyl)-1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid), an asymmetrical derivative of H4dota (=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) substituted at one acetate pendant arm

T2 - 1H-NMR and potentiometric studies of the ligand and its lanthanide(III) complexes

AU - André, João P.

AU - Brücher, E.

AU - Király, R.

AU - Carvalho, Rui A.

AU - Mäcke, Helmut

AU - Geraldes, Carlos F G C

PY - 2005

Y1 - 2005

N2 - The ligand H5dotasa (=(αRS)-α-(carboxymethyl)-1,4,7, 10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) is a H4dota-like macrocyclic ligand with a carboxymethyl CH2COOH substituent at the C(α) atom of one of the four acetate pendant arms of H4dota (=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), present as a racemic mixture of (αR) and (αS) enantiomers. The protonation constants of the ligand were determined by potentiometry, giving values close to those of H4dota except for the extra pK3 value of 5.35 assigned to protonation of the extra carboxylate group in the α-substituted (=succinic acid) pendant arm. The 1H-NMR spectra of H5dotasa at different pH values are too complex to allow the determination of its microscopic protonation scheme, due to the presence of multiple isomeric structures in solution. The thermodynamic stability constant of its Gd3+ chelate was determined by a potentiometric method, and the value obtained, log KML = 27.2 (0.2), is higher than for the [Gd(dota)(OH2)]- complex. The solution structure of the asymmetric Ln3+ chelates of dotasa was studied by 1H-NMR spectroscopy, indicating the presence of four isomers, corresponding to the combination of the antiprismatic (M) and twisted antiprismatic (M) helicities of the pendant arms and to the (αR) and (αS) configurations at the substituted pendant arm. The m/M isomer ratio decreases along the lanthanide series, with the m isomer decreasing from 90% at La to ca. 50% from Eu-Lu. This shows that the expected m isomer population of the [Gd(dotasa)(OH 2)]2- complex is higher than for the unsubstituted [Gd(dota)(OH2)]- (ca. 15%) but lower than for a Gd 3+ chelate of an α,α′,α″, α‴-tetrasubstituted (RRRR)-configurated dota (ca. 70%). Thus the stabilization of the m isomer by C monosubstitution at the dota acetate pendant arm in [Gd(dotasa)(OH2)]2- is responsible for its increased H2O-exchange rate and higher relaxivity.

AB - The ligand H5dotasa (=(αRS)-α-(carboxymethyl)-1,4,7, 10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) is a H4dota-like macrocyclic ligand with a carboxymethyl CH2COOH substituent at the C(α) atom of one of the four acetate pendant arms of H4dota (=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), present as a racemic mixture of (αR) and (αS) enantiomers. The protonation constants of the ligand were determined by potentiometry, giving values close to those of H4dota except for the extra pK3 value of 5.35 assigned to protonation of the extra carboxylate group in the α-substituted (=succinic acid) pendant arm. The 1H-NMR spectra of H5dotasa at different pH values are too complex to allow the determination of its microscopic protonation scheme, due to the presence of multiple isomeric structures in solution. The thermodynamic stability constant of its Gd3+ chelate was determined by a potentiometric method, and the value obtained, log KML = 27.2 (0.2), is higher than for the [Gd(dota)(OH2)]- complex. The solution structure of the asymmetric Ln3+ chelates of dotasa was studied by 1H-NMR spectroscopy, indicating the presence of four isomers, corresponding to the combination of the antiprismatic (M) and twisted antiprismatic (M) helicities of the pendant arms and to the (αR) and (αS) configurations at the substituted pendant arm. The m/M isomer ratio decreases along the lanthanide series, with the m isomer decreasing from 90% at La to ca. 50% from Eu-Lu. This shows that the expected m isomer population of the [Gd(dotasa)(OH 2)]2- complex is higher than for the unsubstituted [Gd(dota)(OH2)]- (ca. 15%) but lower than for a Gd 3+ chelate of an α,α′,α″, α‴-tetrasubstituted (RRRR)-configurated dota (ca. 70%). Thus the stabilization of the m isomer by C monosubstitution at the dota acetate pendant arm in [Gd(dotasa)(OH2)]2- is responsible for its increased H2O-exchange rate and higher relaxivity.

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U2 - 10.1002/hlca.200590044

DO - 10.1002/hlca.200590044

M3 - Article

VL - 88

SP - 633

EP - 646

JO - Helvetica Chimica Acta

JF - Helvetica Chimica Acta

SN - 0018-019X

IS - 3

ER -