title: Development of a new epidermal growth factor receptor positron emission tomography imaging agent based on the 3-cyanoquinoline core: synthesis and biological evaluation.
abstract: The epidermal growth factor receptor (EGFR/c-ErbB1/HER1) is overexpressed in many cancers including breast, ovarian, endometrial, and non-small cell lung cancer. An EGFR specific imaging agent could facilitate clinical evaluation of primary tumors and/or metastases. To achieve this goal we designed and synthesized a small array of fluorine containing compounds based on a 3-cyanoquinoline core. A lead compound, 16, incorporating 2'-fluoroethyl-1,2,3-triazole was selected for evaluation as a radioligand based on its high affinity for EGFR kinase (IC50=1.81+/-0.18 nM), good cellular potency (IC50=21.97+/-9.06 nM), low lipophilicity and good metabolic stability. 'Click' labeling afforded [18F]16 in 37.0+/-3.6% decay corrected radiochemical yield based on azide [18F]14 and 7% end of synthesis (EOS) yield from aqueous fluoride. Compound [18F]16 was obtained with >99% radiochemical purity in a total synthesis time of 3 h. The compound showed good stability in vivo and a fourfold higher uptake in high EGFR expressing A431 tumor xenografts compared to low EGFR expressing HCT116 tumor xenografts. Furthermore, the radiotracer could be visualized in A431 tumor bearing mice by small animal PET imaging. Compound [18F]16 therefore constitutes a promising radiotracer for further evaluation for imaging of EGFR status.
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Chemistry, Imperial College London, Faculty of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom. f.pisaneschi@imperial.ac.uk
authors.forename: Federica
authors.initials: F
authors.lastname: Pisaneschi
authors.forename: Quang-De
authors.initials: QD
authors.lastname: Nguyen
authors.forename: Elham
authors.initials: E
authors.lastname: Shamsaei
authors.forename: Matthias
authors.initials: M
authors.lastname: Glaser
authors.forename: Edward
authors.initials: E
authors.lastname: Robins
authors.forename: Maciej
authors.initials: M
authors.lastname: Kaliszczak
authors.forename: Graham
authors.initials: G
authors.lastname: Smith
authors.forename: Alan C
authors.initials: AC
authors.lastname: Spivey
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D051379:Mice; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics
chemical_list: C554527:4-((1-(2-fluoroethyl)-1H-(1,2,3)triazol-4-ylmethyl)amino)but-2-enoic acid (4-(3-chloro-4-fluorophenylamino)-3-cyano-7-ethoxyquinolin-6-yl)amide; D000634:Aminoquinolines; D005462:Fluorine Radioisotopes; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D019275:Radiopharmaceuticals; D014230:Triazoles; C037219:quinoline; D066246:ErbB Receptors