title: Novel carbon-11 labeled 4-dimethylamino-but-2-enoic acid [4-(phenylamino)-quinazoline-6-yl]-amides: potential PET bioprobes for molecular imaging of EGFR-positive tumors.
abstract: We have previously reported of labeled reversible and irreversible EGFR inhibitors, such as 4-(3,4-dichloro-6-fluoroanilino)-6,7-dimethoxyquinazoline (ML01) and 6-acrylamido-4-(3,4-dichloro-6-fluoroanilino)quinazoline (ML03), to be suboptimal as imaging agents. On the basis of these studies, a new generation of novel, more chemically stable irreversible inhibitors was labeled with carbon-11 as potential positron emission tomography (PET) biomarkers for molecular imaging of epidermal growth factor receptor (EGFR)-positive tumors. In these new labeled, irreversible inhibitors the acryl-amide group at the 6-position of the quinazoline ring was replaced with a 4-dimethylamino-but-2-enoic amide. The nonlabeled compounds were evaluated in vitro to determine their EGFR autophosphorylation IC(50) values. The IC(50) values indicated that these new irreversible compounds possess similar potencies towards the EGFR, as the parent compound, ML03. These compounds were labeled with carbon-11 at the dimethylamine moiety, using the well known labeling reagent C-11 MeI. The labeling procedure was automated using a commercial module. The final products were obtained with 10% decay corrected radiochemical yield, 99% radiochemical purity, 96% chemical purity, and a high specific activity of 2.7 Ci/micromol EOB. The high potency of these new labeled bioprobes towards the EGFR establishes their potential to serve as PET agents for molecular imaging of EGFR-positive tumors.
authors.affiliation: Department of Nuclear Medicine, Hadassah Hebrew University Hospital, P.O.B. 12000, Jerusalem 91120, Israel. mishani@md2.huji.ac.il
authors.forename: Eyal
authors.initials: E
authors.lastname: Mishani
authors.forename: Galith
authors.initials: G
authors.lastname: Abourbeh
authors.forename: Yulia
authors.initials: Y
authors.lastname: Rozen
authors.forename: Orit
authors.initials: O
authors.lastname: Jacobson
authors.forename: Desideriu
authors.initials: D
authors.lastname: Laky
authors.forename: Iris
authors.initials: I
authors.lastname: Ben David
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
authors.forename: Mazal
authors.initials: M
authors.lastname: Shaul
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism*; D005240:Feasibility Studies; D006801:Humans; D015335:Molecular Probes / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011799:Quinazolines / Q000737:chemistry / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed / Q000379:methods
chemical_list: D014408:Biomarkers, Tumor; D002250:Carbon Radioisotopes; D015335:Molecular Probes; D011799:Quinazolines; D019275:Radiopharmaceuticals; D066246:ErbB Receptors