Synthesis of novel 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA) derivatives for chemoselective attachment to unprotected polyfunctionalized compounds

Chemistry. 2007;13(21):6082-90. doi: 10.1002/chem.200700231.

Abstract

A convenient synthesis of novel bifunctional poly(amino carboxylate) chelating agents allowing chemoselective attachment to highly functionalized biomolecules is described. Based on the well known chelator 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA), we synthesized novel bifunctional chelating agents bearing additional functional groups by alkylating 1,4,7,10-tetraazacyclododecane (cyclen) with one equivalent of para-functionalized alkyl 2-bromophenyl-acetate and three equivalents of tert-butyl 2-bromoacetate. The resulting compounds, which contain an additional carbonyl or alkyne functionality, allow site specific labeling of appropriately functionalized unprotected biomolecules in a rapid manner via click reactions. This was demonstrated by the attachment of our new DOTA derivatives to the somatostatin analogue Tyr3-octreotate by chemoselective oxime ligation and CuI-catalyzed azide-alkyne cycloaddition. Initial biodistribution studies in mice with the radiometalated compound demonstrated the applicability of the described DOTA conjugation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes / chemistry
  • Amination
  • Animals
  • Azides / chemistry
  • Carbonic Acid / chemistry
  • Catalysis
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Copper / chemistry
  • Cyclization
  • Female
  • Heterocyclic Compounds, 1-Ring / chemical synthesis
  • Heterocyclic Compounds, 1-Ring / chemistry*
  • Heterocyclic Compounds, 1-Ring / pharmacokinetics
  • Heterocyclic Compounds, 1-Ring / therapeutic use
  • Ketones / chemistry
  • Mice
  • Mice, Nude
  • Molecular Structure
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Oximes / chemistry
  • Oxygen / chemistry
  • Peptides / chemistry
  • Rats
  • Tyrosine / chemistry
  • Xenograft Model Antitumor Assays

Substances

  • Alkynes
  • Azides
  • Heterocyclic Compounds, 1-Ring
  • Ketones
  • Oximes
  • Peptides
  • 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
  • Tyrosine
  • Carbonic Acid
  • Copper
  • Oxygen