title: Evaluation of radiolabeled ML04, a putative irreversible inhibitor of epidermal growth factor receptor, as a bioprobe for PET imaging of EGFR-overexpressing tumors.
abstract: Overexpression of epidermal growth factor receptor (EGFR) has been implicated in tumor development and malignancy. Evaluating the degree of EGFR expression in tumors could aid in identifying patients for EGFR-targeted therapies and in monitoring treatment. Nevertheless, no currently available assay can reliably quantify receptor content in tumors. Radiolabeled inhibitors of EGFR-TK could be developed as bioprobes for positron emission tomography imaging. Such imaging agents would not only provide a noninvasive quantitative measurement of EGFR content in tumors but also serve as radionuclide carriers for targeted radiotherapy. The potency, reversibility, selectivity and specific binding characteristics of ML04, an alleged irreversible inhibitor of EGFR, were established in vitro. The distribution of the F-18-labeled compound and the extent of EGFR-specific tumor uptake were evaluated in tumor-bearing mice. ML04 demonstrated potent, irreversible and selective inhibition of EGFR, combined with specific binding to the receptor in intact cells. In vivo distribution of the radiolabeled compound revealed tumor/blood and tumor/muscle activity uptake ratios of about 7 and 5, respectively, 3 h following administration of a radiotracer. Nevertheless, only minor EGFR-specific uptake of the compound was detected in these studies, using either EGFR-negative tumors or blocking studies as controls. To improve the in vivo performance of ML04, administration via prolonged intravenous infusion is proposed. Detailed pharmacokinetic characterization of this bioprobe could assist in the development of a kinetic model that would afford accurate measurement of EGFR content in tumors.
authors.affiliation: Department of Medical Biophysics and Nuclear Medicine, Hadassah Hebrew University, Jerusalem 91120, Israel.
authors.forename: Galith
authors.initials: G
authors.lastname: Abourbeh
authors.forename: Samar
authors.initials: S
authors.lastname: Dissoki
authors.forename: Orit
authors.initials: O
authors.lastname: Jacobson
authors.forename: Amir
authors.initials: A
authors.lastname: Litchi
authors.forename: Revital
authors.initials: R
authors.lastname: Ben Daniel
authors.forename: Desirediu
authors.initials: D
authors.lastname: Laki
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
authors.forename: Eyal
authors.initials: E
authors.lastname: Mishani
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000000981:diagnostic imaging* / Q000378:metabolism*; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D015336:Molecular Probe Techniques; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D011799:Quinazolines / Q000737:chemistry / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; C518595:N-(4-((4,5-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)-4-dimethylamino-2-butenamide; D011799:Quinazolines; D019275:Radiopharmaceuticals; D066246:ErbB Receptors