Lawrence Berkeley National Laboratory

The goal of this research was to develop epidermal growth factor receptor (EGFR) nuclear medicine breast cancer imaging agents. Our approach was to synthesize small molecule inhibitors of the EGFR tyrosine kinase (tk) suitable for labeling with single photon or positron-emitting radioisotopes and evaluate the imaging potential of these new molecules. We have synthesized and fully characterized 22 quinazoline compounds. All compounds inhibit EGFR tk phosphorylation activity in the nanomolar range. All compounds tested exhibited specificity for the EGFR tk versus the ErbB2 and ErbB4 tyrosine kinases. A radiometric binding assay using an iodine-125 labeled quinazoline was developed to determine the affinity of the quinazolines for the EGFR tk ATP binding site. The affinities ranged from 0.4-51 nM. The octanol/water partition coefficients (Log P; lipophilicity) of the new compounds ranged from 2.2-5.5. Six compounds have been labeled with fluorine-18. Biodistribution in EGFR overexpressing tumor bearing mice demonstrated tumor uptake but highlighted delivery and metabolism issues. The 2-fluoro quinazoline was not metabolized in an in vitro hepatocyte study. From this work a breadth of agent characteristics was created establishing the foundation for future research toward the optimal EGFR imaging agent.