title: Novel iodine-124 labeled EGFR inhibitors as potential PET agents for molecular imaging in cancer.
abstract: The in vivo results with our previously reported irreversible labeled inhibitor [(11)C]-ML03 suggested that more chemically stable inhibitors, labeled with a longer-lived radioisotope, could be better candidates for molecular imaging of epidermal growth factor receptor (EGFR) positive tumors. On the basis of this hypothesis we synthesized three new irreversible tyrosine kinase (TK) inhibitors with various chemical reactivities. The three new inhibitors were successfully labeled on the anilino moiety with [(124)I], starting with the 6-amino-4-[(3-tributylstannylphenyl)amino]-quinazoline (9) precursor. The cell-free results, obtained with these new irreversible inhibitors, indicated that compounds 5 (alpha-chloro-acetamide derivative) and 6 (4-dimethylamino-but-2-enoic amide derivative) possessed high potencies toward the EGFR with an irreversible inhibition effect. Compound 4 (alpha-methoxy-acetamide derivative) was found to be less potent, with only a partially irreversible effect. The high potency of compounds 5 and 6 toward the EGFR establishes their potential as PET agents for molecular imaging of EGFR positive tumors. Their prospect as PET biomarkers is further being investigated.
authors.affiliation: Department of Medical Biophysics and Nuclear Medicine, Hadassah Hebrew University, Hadassah Hospital, Jerusalem 91120, Israel.
authors.forename: Mazal
authors.initials: M
authors.lastname: Shaul
authors.forename: Galith
authors.initials: G
authors.lastname: Abourbeh
authors.forename: Orit
authors.initials: O
authors.lastname: Jacobson
authors.forename: Yulia
authors.initials: Y
authors.lastname: Rozen
authors.forename: Desideriu
authors.initials: D
authors.lastname: Laky
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
authors.forename: Eyal
authors.initials: E
authors.lastname: Mishani
mesh_terms: D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007457:Iodine Radioisotopes; D015394:Molecular Structure; D009369:Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000295:instrumentation*
chemical_list: D004791:Enzyme Inhibitors; D007457:Iodine Radioisotopes; D066246:ErbB Receptors