Improved syntheses and applicability of different DOTA building blocks for multiply derivatized scaffolds

Bioorg Med Chem. 2008 Mar 1;16(5):2606-16. doi: 10.1016/j.bmc.2007.11.044. Epub 2007 Nov 22.

Abstract

DOTA (1,4,7,10-tetraazacyclodocecane-N,N',N'',N'''-tetraacetic acid), which forms extremely stable complexes with a large number of metal ions, is one of the most important and most commonly used chelators for in vivo applications such as cancer diagnosis and therapy. However, many of the published synthesis protocols for DOTA derivatives are complicated and give the products in low yields. Here we report improved synthesis routes for tris-tBu-DOTA, tris-benzyl-DOTA, and thiol-DOTA, and also describe the synthesis of the novel compound tris-4-nitro-benzyl-DOTA. In addition, we determined the applicability of the DOTA derivatives tris-tBu-DOTA, thiol-DOTA, tris-benzyl-DOTA, tris-4-nitrobenzyl-DOTA, tris-allyl-DOTA, DOTA-PFP-ester, and DOTA-PNP-ester for multimerization reactions using amino functionalized PAMAM dendrimers of different sizes. Thiol-DOTA was found to be the best compound for efficient reactions with dendritic scaffolds generating highly homogeneous DOTA-multimers. This DOTA derivative could be quantitatively conjugated to a 128-mer dendrimer.

MeSH terms

  • Butanes / chemistry
  • Chromatography, High Pressure Liquid
  • Heterocyclic Compounds, 1-Ring / chemical synthesis*
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Molecular Structure
  • Nitrobenzenes / chemistry
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Sulfhydryl Compounds / chemistry

Substances

  • Butanes
  • Heterocyclic Compounds, 1-Ring
  • Nitrobenzenes
  • Sulfhydryl Compounds
  • 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
  • butane
  • nitrobenzene