Synthesis and evaluation of two new bifunctional carboxymethylated tetraazamacrocyclic chelating agents for protein labeling with indium-111

Bioconjug Chem. 1990 Sep-Oct;1(5):345-9. doi: 10.1021/bc00005a008.

Abstract

The synthesis of two new N- and C-functionalized tetraazamacrocyclic ligands intended to be covalently linked to biomolecules like monoclonal antibodies and to bind the gamma-emitting isotope indium-111 in a thermodynamically and/or kinetically inert way is described. 12-(p-Nitrobenzyl)-1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetraa cetic acid (L1) was synthesized by means of bimolecular cyclization with the appropriate malonic acid diethyl ester and triethylenetetraamine, followed by reduction with diborane and alkylation of the cyclic tetraamine with bromoacetic acid. The corresponding triscarboxymethylated ligand L2 was made by statistical alkylation of the tetraamine. Both ligands fulfill the criteria for antibody labeling using the bifunctional chelate approach, namely fast chelate formation, high radiochemical yield, and high stability under physiological conditions. Surprisingly the heptadentate ligand L2 confers higher stability to In3+ and exhibits faster complex formation than octadentate L1. 13C NMR spectra in solution indicate that the difference in stability is not due to incomplete coordination of all four carboxylate groups in In-L1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / chemical synthesis*
  • Acetates / chemistry
  • Chemical Phenomena
  • Chemistry
  • Cross-Linking Reagents / chemical synthesis*
  • Drug Stability
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Humans
  • Indium Radioisotopes* / blood
  • Isotope Labeling*
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Nitrobenzenes
  • Spectrum Analysis
  • Transferrin / metabolism

Substances

  • Acetates
  • Cross-Linking Reagents
  • Heterocyclic Compounds
  • Indium Radioisotopes
  • Nitrobenzenes
  • Transferrin
  • 12-(4-nitrobenzyl)-1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetraacetic acid
  • 12(4-nitrobenzyl)-1,4,7,10-tetraazacyclotridecane-1,4,7-triacetic acid