title: Radiohalogenated 4-anilinoquinazoline-based EGFR-TK inhibitors as potential cancer imaging agents.
abstract: BACKGROUND
  The overexpression of epidermal growth factor receptor (EGFR) in tumors underlines the recent interest in EGFR as attractive target for the development of new cancer imaging agents. EGFR-tyrosine kinase inhibitors (EGFR-TKIs) based on the anilinoquinazoline scaffold have been explored as potential probes for EGFR imaging. However, up to now, no optimal radiotracer is available. Herein, we report the synthesis and biological evaluation of three novel halogenated 6-substituted 4-anilinoquinazoline based EGFR-TKIs. Radiosynthesis ((125)I and (18)F) of the corresponding analogues was also performed.
  
  
  METHODS
  6a, 6b and 8 were obtained by reaction of 6-amino-4-anilinoquinazoline (5) with 3-/4-iodobenzoyl and 4-fluorobenzoyl chlorides. Inhibition of EGFR autophosphorylation and A431 cellular proliferation were assessed by Western blot and MTT assays. (125)I-anilinoquinazolines [(125)I]6a/b were prepared via destannylation of the corresponding tributylstannyl precursors with [(125)I]NaI. Cellular uptake studies were conducted in A431 cells. Optimization of the radiosynthesis of the (18)F-anilinoquinazoline [(18)F]8 was attempted by nucleophilic substitution of the trimethylammonium- and nitro-6-substituted 4-anilinoquinazoline precursors.
  
  
  RESULTS
  6a, 6b and 8 were synthesized in high chemical yield. All of them are inhibitors of EGFR autophosphorylation (0.1<IC(50)<1 μM) and A431 cell proliferation (IC(50)<3.5 μM). [(125)I]6a/b, obtained in high radiochemical purity and specific activity, were highly taken up by A431 cells. Biodistribution profile in mice indicated fast blood clearance and hepatobiliary excretion. Despite all attempts, [(18)F]8 was only formed in 4% yield, hampering further biological evaluation.
  
  
  CONCLUSIONS
  This study suggests that these quinazoline derivatives can act as EGFR-TKI, warranting further modifications in the chemical structure in order to be explored as potential molecular imaging agents for single photon emission computerized tomography and positron emission tomography.
authors.affiliation: Unidade de Ciências Químicas e Radiofarmacêuticas, Instituto Tecnológico e Nuclear, Estrada Nacional 10, 2686-953 Sacavém, Portugal.
authors.forename: Carina
authors.initials: C
authors.lastname: Neto
authors.forename: Célia
authors.initials: C
authors.lastname: Fernandes
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Oliveira
authors.forename: Lurdes
authors.initials: L
authors.lastname: Gano
authors.forename: Filipa
authors.initials: F
authors.lastname: Mendes
authors.forename: Torsten
authors.initials: T
authors.lastname: Kniess
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics* / Q000494:pharmacology; D054879:Halogenation; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D011877:Radionuclide Imaging; D014018:Tissue Distribution; D014846:Vulvar Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D007457:Iodine Radioisotopes; D011799:Quinazolines; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases