title: Anilinodialkoxyquinazolines: screening epidermal growth factor receptor tyrosine kinase inhibitors for potential tumor imaging probes.
abstract: The epidermal growth factor receptor (EGFR), a long-standing drug development target, is also a desirable target for imaging. Sixteen dialkoxyquinazoline analogues, suitable for labeling with positron-emitting isotopes, have been synthesized and evaluated in a battery of in vitro assays to ascertain their chemical and biological properties. These characteristics provided the basis for the adoption of a selection schema to identify lead molecules for labeling and in vivo evaluation. A new EGFR tyrosine kinase radiometric binding assay revealed that all of the compounds possessed suitable affinity (IC50 = 0.4-51 nM) for the EGFR tyrosine kinase. All of the analogues inhibited ligand-induced EGFR tyrosine phosphorylation (IC50 = 0.8-20 nM). The HPLC-estimated octanol/water partition coefficients ranged from 2 to 5.5. Four compounds, 4-(2'-fluoroanilino)- and 4-(3'-fluoroanilino)-6,7-diethoxyquinazoline as well as 4-(3'-chloroanilino)- and 4-(3'-bromoanilino)-6,7-dimethoxyquinazoline, possess the best combination of characteristics that warrant radioisotope labeling and further evaluation in tumor-bearing mice.
authors.affiliation: Department of Functional Imaging, Lawrence Berkeley National Laboratory, Berkeley, California 94720-8119, USA. hfvanbrocklin@lbl.gov
authors.forename: Henry F
authors.initials: HF
authors.lastname: VanBrocklin
authors.forename: John K
authors.initials: JK
authors.lastname: Lim
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Coffing
authors.forename: Darren L
authors.initials: DL
authors.lastname: Hom
authors.forename: Kitaw
authors.initials: K
authors.lastname: Negash
authors.forename: Michele Y
authors.initials: MY
authors.lastname: Ono
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gilmore
authors.forename: Ianthe
authors.initials: I
authors.lastname: Bryant
authors.forename: David J
authors.initials: DJ
authors.lastname: Riese
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002250:Carbon Radioisotopes; D002460:Cell Line; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005462:Fluorine Radioisotopes; D006801:Humans; D007553:Isotope Labeling; D008024:Ligands; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging; D010766:Phosphorylation; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D066247:Receptor, ErbB-4; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D002250:Carbon Radioisotopes; D004247:DNA; D066246:ErbB Receptors; D005462:Fluorine Radioisotopes; D008024:Ligands; D011799:Quinazolines; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D014443:Tyrosine; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse