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

We have previously reported of labeled reversible and irreversible EGFR inhibitors, such as 4-(3,4-dichloro-6-fluoroanilino)-6,7dimethoxyquinazoline (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 IC50 values. The IC50 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 Mel. 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/mumol EOB. The high potency of these new labeled bioprobes towards the EGFR-positive tumors. (C) 2004 Elsevier Inc. All rights reserved.