Improved synthesis of DOTA tetraamide ligands for lanthanide(III) ions

A tool for increasing the repertoire of potential PARACEST contrast agents for MRI and/or fluorescent sensors

Luis M. De León-Rodríguez, Subha Viswanathan, A. Dean Sherry

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The synthesis of new DOTA tetraamide (DOTAMR4) compounds is of great interest given their application in the formation of Ln(III) complexes as potential PARACEST contrast agents in MRI or fluorescent molecular probes. In this context amino acid and peptide DOTAMR4 derivatives are particularly attractive since the amino-acid and/or peptide moiety can show responsive properties dependent on a given stimuli which might translate to changes in water exchange rates of the corresponding Ln(III) complex. Current synthesis of DOTAMR4 derivatives is typically carried out by reacting haloacetamide intermediates with cyclen. However, this method fails to generate the tetra-substituted products when bulky substituents are present in the haloacetamide and in some cases this intermediate cannot be prepared by conventional acylation procedures limiting the number of DOTAMR4 compounds available for study. As a solution to these limitations, an improved methodology for the synthesis of DOTAMR4 by coupling DOTA to an appropriate amine containing reagent (i.e. protected amino-acids with the α-amino group free) is presented in this work. Several DOTAMR4 derivatives which are difficult or impossible to prepare with the traditional methodologies were easily obtained starting with DOTA. A new protocol was derived using this methodology for the solution-phase synthesis of DOTA peptide derivatives. With this methodology, many other DOTAMR4 peptide and non-peptide derivatives have been prepared in our laboratories with several of these new compounds showing interesting properties for molecular imaging.

Original languageEnglish (US)
Pages (from-to)121-125
Number of pages5
JournalContrast Media and Molecular Imaging
Volume5
Issue number3
DOIs
StatePublished - May 2010

Fingerprint

Lanthanoid Series Elements
Contrast Media
Ions
Ligands
Peptides
Amino Acids
Molecular Probes
Molecular Imaging
Acylation
Fluorescent Dyes
Amines
Water

Keywords

  • Amide
  • DOTA
  • Molecular sensors
  • MRI
  • PARACEST agents
  • Peptide
  • Synthesis

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

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title = "Improved synthesis of DOTA tetraamide ligands for lanthanide(III) ions: A tool for increasing the repertoire of potential PARACEST contrast agents for MRI and/or fluorescent sensors",
abstract = "The synthesis of new DOTA tetraamide (DOTAMR4) compounds is of great interest given their application in the formation of Ln(III) complexes as potential PARACEST contrast agents in MRI or fluorescent molecular probes. In this context amino acid and peptide DOTAMR4 derivatives are particularly attractive since the amino-acid and/or peptide moiety can show responsive properties dependent on a given stimuli which might translate to changes in water exchange rates of the corresponding Ln(III) complex. Current synthesis of DOTAMR4 derivatives is typically carried out by reacting haloacetamide intermediates with cyclen. However, this method fails to generate the tetra-substituted products when bulky substituents are present in the haloacetamide and in some cases this intermediate cannot be prepared by conventional acylation procedures limiting the number of DOTAMR4 compounds available for study. As a solution to these limitations, an improved methodology for the synthesis of DOTAMR4 by coupling DOTA to an appropriate amine containing reagent (i.e. protected amino-acids with the α-amino group free) is presented in this work. Several DOTAMR4 derivatives which are difficult or impossible to prepare with the traditional methodologies were easily obtained starting with DOTA. A new protocol was derived using this methodology for the solution-phase synthesis of DOTA peptide derivatives. With this methodology, many other DOTAMR4 peptide and non-peptide derivatives have been prepared in our laboratories with several of these new compounds showing interesting properties for molecular imaging.",
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AU - De León-Rodríguez, Luis M.

AU - Viswanathan, Subha

AU - Sherry, A. Dean

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N2 - The synthesis of new DOTA tetraamide (DOTAMR4) compounds is of great interest given their application in the formation of Ln(III) complexes as potential PARACEST contrast agents in MRI or fluorescent molecular probes. In this context amino acid and peptide DOTAMR4 derivatives are particularly attractive since the amino-acid and/or peptide moiety can show responsive properties dependent on a given stimuli which might translate to changes in water exchange rates of the corresponding Ln(III) complex. Current synthesis of DOTAMR4 derivatives is typically carried out by reacting haloacetamide intermediates with cyclen. However, this method fails to generate the tetra-substituted products when bulky substituents are present in the haloacetamide and in some cases this intermediate cannot be prepared by conventional acylation procedures limiting the number of DOTAMR4 compounds available for study. As a solution to these limitations, an improved methodology for the synthesis of DOTAMR4 by coupling DOTA to an appropriate amine containing reagent (i.e. protected amino-acids with the α-amino group free) is presented in this work. Several DOTAMR4 derivatives which are difficult or impossible to prepare with the traditional methodologies were easily obtained starting with DOTA. A new protocol was derived using this methodology for the solution-phase synthesis of DOTA peptide derivatives. With this methodology, many other DOTAMR4 peptide and non-peptide derivatives have been prepared in our laboratories with several of these new compounds showing interesting properties for molecular imaging.

AB - The synthesis of new DOTA tetraamide (DOTAMR4) compounds is of great interest given their application in the formation of Ln(III) complexes as potential PARACEST contrast agents in MRI or fluorescent molecular probes. In this context amino acid and peptide DOTAMR4 derivatives are particularly attractive since the amino-acid and/or peptide moiety can show responsive properties dependent on a given stimuli which might translate to changes in water exchange rates of the corresponding Ln(III) complex. Current synthesis of DOTAMR4 derivatives is typically carried out by reacting haloacetamide intermediates with cyclen. However, this method fails to generate the tetra-substituted products when bulky substituents are present in the haloacetamide and in some cases this intermediate cannot be prepared by conventional acylation procedures limiting the number of DOTAMR4 compounds available for study. As a solution to these limitations, an improved methodology for the synthesis of DOTAMR4 by coupling DOTA to an appropriate amine containing reagent (i.e. protected amino-acids with the α-amino group free) is presented in this work. Several DOTAMR4 derivatives which are difficult or impossible to prepare with the traditional methodologies were easily obtained starting with DOTA. A new protocol was derived using this methodology for the solution-phase synthesis of DOTA peptide derivatives. With this methodology, many other DOTAMR4 peptide and non-peptide derivatives have been prepared in our laboratories with several of these new compounds showing interesting properties for molecular imaging.

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