A useful EGFR-TK ligand for tumor diagnosis with SPECT: development of radioiodinated 6-(3-morpholinopropoxy)-7-ethoxy-4-(3′-iodophenoxy)quinazoline

OBJECTIVE: Epidermal growth factor receptor tyrosine kinase (EGFR-TK) represents an attractive target for tumor diagnosis agents. Previously, radioiodinated 4-(3-iodophenoxy)-6,7-diethoxyquinazoline (PHY) was reported to possess good characteristics as a tumor imaging agent. We have explored the feasibility of developing tumor diagnosis ligands superior to radioiodinated PHY. METHODS: New phenoxyquinazoline derivatives were designed with various side chains introduced to the 6th position of PHY. The IC(50) values of the new derivatives to interrupt EGFR-TK phosphorylation were evaluated and compared to well-known EGFR-TK inhibitors. Tumor uptake studies of the new (125)I-labeled derivatives were conducted with A431 tumor-bearing mice. Selectivity and binding characteristics were analyzed by in vitro blocking studies and a binding assay. Furthermore, SPECT/CT scans were performed using A431 tumor-bearing mice. RESULTS: Six quinazoline derivatives were designed and synthesized, and among these, 6a–d were found to have relatively high EGFR-TK inhibitory potency. In tumor uptake studies, [(125)I]6a ([(125)I]PYK) was found to have the highest tumor uptake and longest retention in tumors. In contrast, [(125)I]PYK was rapidly cleared from peripheral tissues, resulting in a high tumor-to-tissue ratio 24 h after injection. Moreover, the EGFR-TK selectivity of [(125)I]PYK was confirmed by pretreatment experiments with specific EGFR-TK inhibitors. Furthermore, [(125)I]PYK provided clear SPECT images of tumors. CONCLUSIONS: Radioiodinated PYK, one of the newly synthesized quinazoline derivatives, was found to be a desirable ligand for EGFR-TK SPECT imaging. [(125)I]PYK showed high tumor accumulation and selective EGFR-TK binding and also succeeded in delivering high contrast imaging of tumors. These favorable characteristics of [(125)I]PYK suggest that the (123)I-labeled counterpart, [(123)I]PYK, would have great potential for diagnostic SPECT tumor imaging.