title: High-affinity epidermal growth factor receptor (EGFR) irreversible inhibitors with diminished chemical reactivities as positron emission tomography (PET)-imaging agent candidates of EGFR overexpressing tumors.
abstract: Previous studies with the anilinoquinazoline epidermal growth factor receptor (EGFR) irreversible inhibitor [(11)C]-ML03 demonstrated a rapid metabolism of the tracer, which led to its low in vivo accumulation in EGFR overexpressing tumors. To enhance tumor uptake, the chemical structure of the compound was modified, and four new groups of EGFR inhibitors with a wide range of chemical reactivities were synthesized. Chemical reactivity assay of the compounds, performed with reduced glutathione (GSH), revealed that the group C (4-(dimethylamino)-but-2-enoic amide) derivative was the least chemically reactive against the nucleophilic attack of GSH. Nonetheless, it demonstrated a high inhibitory potency and bound irreversibly to the EGFR. Consequently, the blood stability of the group C compound (5a, ML04) labeled with (11)C was studied. In a time frame of 60 min, no radioactive metabolites were detected in blood. The stability of [(11)C]-5a, as indicated both from in vitro blood-stability assays and injection into nude rats, was significantly higher as compared to [(11)C]-ML03. Since group C presented a greater promise for tumor accumulation, it represents, to date, the most suitable candidate for radiolabeling with long-lived positron emission tomography (PET) radioisotopes.
authors.affiliation: Department of Medical Biophysics and Nuclear Medicine, Hadassah Hebrew University, Jerusalem 91120, Israel. mishani@md.huji.ac.il
authors.forename: Eyal
authors.initials: E
authors.lastname: Mishani
authors.forename: Galith
authors.initials: G
authors.lastname: Abourbeh
authors.forename: Orit
authors.initials: O
authors.lastname: Jacobson
authors.forename: Samar
authors.initials: S
authors.lastname: Dissoki
authors.forename: Revital
authors.initials: R
authors.lastname: Ben Daniel
authors.forename: Yulia
authors.initials: Y
authors.lastname: Rozen
authors.forename: Mazal
authors.initials: M
authors.lastname: Shaul
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D002460:Cell Line; D004355:Drug Stability; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011923:Rats, Nude; D013329:Structure-Activity Relationship
chemical_list: D002250:Carbon Radioisotopes; D011799:Quinazolines; D019275:Radiopharmaceuticals; D066246:ErbB Receptors; D005978:Glutathione