A quinazoline-derivative DOTA-type gallium(III) complex for targeting epidermal growth factor receptors: synthesis, characterisation and biological studies

J Biol Inorg Chem. 2009 Feb;14(2):261-71. doi: 10.1007/s00775-008-0446-8. Epub 2008 Nov 13.

Abstract

The novel DOTA-like chelator 1,4,7,10-tetraazacyclododecane-1-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}propionamide-4,7,10-triacetic acid (H(3)L) was synthesised by alkylation of 1,4,7,10-tetraazacyclododecane-1,4,7-tris(t-butyl acetate) with N-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-bromopropionamide, followed by hydrolysis of the ester groups with trifluoracetic acid. H(3)L has been fully characterised by multinuclear NMR spectroscopy, mass spectrometry and high-performance liquid chromatography (HPLC). Five protonation constants, log K (Hi ), of H(3)L were determined by potentiometry and UV-vis spectrophotometry and the values found are 10.47, 9.18, 5.24, 4.00 and 2.23. These methods, complemented with variable-pH (71)Ga NMR studies, allowed us to ascertain the stability constant of the Ga(III) complex of L. GaL has a remarkably high thermodynamic stability constant (log K (ML) = 24.5). The radioactive complex (67)GaL was prepared in high yield and high radiochemical purity. Its HPLC chromatogram is identical to that obtained for the GaL complex prepared at the macroscopic level. At pH 7.4, (67)GaL has an overall neutral charge, is highly hydrophilic (log D = -1.02 +/- 0.03) and presents high in vitro stability in physiological media and in the presence of an excess of diethylenetriaminepentaethanoic acid . In vitro studies indicated that H(3)L and GaL do not inhibit the cell growth of epidermal growth factor receptor expressing cell lines, such as A431 cervical carcinoma cells, a result which agrees with the very low cell internalisation found for (67)GaL in the same cell line. Biodistribution studies in mice indicated high in vivo stability for (67)GaL, a high total excretion rate and a relatively slow blood clearance, in full accordance with its hydrophilic character and the relatively important protein binding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Animals
  • Cell Line, Tumor
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Female
  • Gallium / chemistry*
  • Heterocyclic Compounds, 1-Ring / chemistry*
  • Humans
  • Hydrolysis
  • Intestines / chemistry
  • Kidney / chemistry
  • Ligands
  • Mice
  • Molecular Structure
  • Organometallic Compounds / chemical synthesis*
  • Organometallic Compounds / chemistry*
  • Organometallic Compounds / pharmacology
  • Quinazolines / chemistry*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Time Factors
  • Tissue Distribution

Substances

  • 1,4,7,10-tetraazacyclododecane-1-(4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)propionamide-4,7,10-triacetic acid
  • Heterocyclic Compounds, 1-Ring
  • Ligands
  • Organometallic Compounds
  • Quinazolines
  • Gallium
  • ErbB Receptors