Development of Novel Epidermal Growth Receptor-Based Radiopharmaceuticals: Imaging Agents for Breast Cancer
Abstract
The goal of this research is to develop epidermal growth factor receptor (EGFR) nuclear medicine breast cancer imaging agents. Our approach is 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 fourteen (14) quinazoline compounds. Most 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. We developed a radiometric binding assay and found that the quinazolines exhibit nanomolar binding affinity for the EGFR tk ATP binding site. The octanol/water partition coefficients (Log P) lipophilicity, of the new compounds ranged from 2.8-5.5. Four compounds have been labeled with fluorine-i 8. Biodistribution of three of the labeled compounds in EGFR overxpressing tumor bearing mice demonstrated tumor uptake but highlighted delivery and metabolism issues. Based on our preliminary results to date, this class of labeled compounds remains promising as a source of EGFR imaging agents for breast tumors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2000
- Accession Number
- ADA389713
Entities
People
- Henry Van Brocklin
Organizations
- University of California, Berkeley