title: A useful EGFR-TK ligand for tumor diagnosis with SPECT: development of radioiodinated 6-(3-morpholinopropoxy)-7-ethoxy-4-(3'-iodophenoxy)quinazoline.
abstract: OBJECTIVE
  Epidermal growth factor receptor tyrosine kinase (EGFR-TK) represents an attractive target for tumor diagnosis agents. Previously, radioiodinated 4-(3-iodophenoxy)-6,7-diethoxyquinazoline (PHY) was reported to possess good characteristics as a tumor imaging agent. We have explored the feasibility of developing tumor diagnosis ligands superior to radioiodinated PHY.
  
  
  METHODS
  New phenoxyquinazoline derivatives were designed with various side chains introduced to the 6th position of PHY. The IC50 values of the new derivatives to interrupt EGFR-TK phosphorylation were evaluated and compared to well-known EGFR-TK inhibitors. Tumor uptake studies of the new (125)I-labeled derivatives were conducted with A431 tumor-bearing mice. Selectivity and binding characteristics were analyzed by in vitro blocking studies and a binding assay. Furthermore, SPECT/CT scans were performed using A431 tumor-bearing mice.
  
  
  RESULTS
  Six quinazoline derivatives were designed and synthesized, and among these, 6a-d were found to have relatively high EGFR-TK inhibitory potency. In tumor uptake studies, [(125)I]6a ([(125)I]PYK) was found to have the highest tumor uptake and longest retention in tumors. In contrast, [(125)I]PYK was rapidly cleared from peripheral tissues, resulting in a high tumor-to-tissue ratio 24 h after injection. Moreover, the EGFR-TK selectivity of [(125)I]PYK was confirmed by pretreatment experiments with specific EGFR-TK inhibitors. Furthermore, [(125)I]PYK provided clear SPECT images of tumors.
  
  
  CONCLUSIONS
  Radioiodinated PYK, one of the newly synthesized quinazoline derivatives, was found to be a desirable ligand for EGFR-TK SPECT imaging. [(125)I]PYK showed high tumor accumulation and selective EGFR-TK binding and also succeeded in delivering high contrast imaging of tumors. These favorable characteristics of [(125)I]PYK suggest that the (123)I-labeled counterpart, [(123)I]PYK, would have great potential for diagnostic SPECT tumor imaging.
authors.affiliation: Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Osaka, Takatsuki 569-1094, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hirata
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Kanai
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Naka
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Shinya
authors.initials: S
authors.lastname: Kagawa
authors.forename: Keiji
authors.initials: K
authors.lastname: Matsumuro
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Katsuma
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Magata
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Ohmomo
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging* / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D008024:Ligands; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D009928:Organ Specificity; D011799:Quinazolines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D007457:Iodine Radioisotopes; D008024:Ligands; D011799:Quinazolines; D019275:Radiopharmaceuticals; D066246:ErbB Receptors