Synthesis and evaluation of radioiodinated phenoxyquinazoline and benzylaminoquinazoline derivatives as new EGF receptor tyrosine kinase imaging ligands for tumor diagnosis using SPECT

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) represents an attractive target for tumor diagnosis agents. Previously, the radioiodinated 4-(3-iodoanilino)-6,7-diethoxyquinazoline ([125I]m-IPQ) has been reported to possess good characteristics as a tumor imaging agent; however, it was also found to have low in vivo stability. To improve the in vivo stability, m-IPQ derivatives, 4-(3-iodophenoxy)-6,7-diethoxyquinazoline (PHY) and 4-(3-iodobenzylamino)-6,7-diethoxyquinazoline (BAY) were designed and synthesized, and the biological studies of [125I]PHY and [125I]BAY were performed to evaluate these new ligands as in vivo tumor diagnosis agents. PHY and BAY were synthesized according to previous reports. The EGFR-TK inhibitory potency of these new compounds was measured and compared to other EGFR-TK inhibitors. Radiolabeled [125I]PHY and [125I]BAY were synthesized by an iododestannylation reaction. Biodistribution studies of these radioligands were conducted in normal mice and tumor-bearing mice. Furthermore, selectivity and binding characteristics of [125I]PHY were analyzed by in vitro blocking studies and a binding assay. The new derivatives were found to have high inhibitory potency against EGFR-TK (PHY: IC50=12.7±7.2 nM, BAY: IC50=51.0±8.9 nM). [125I]PHY and [125I]BAY were conveniently synthesized from tributylstannyl precursors. In in vivo biodistribution studies, [125I]PHY and [125I]BAY were observed to have lower uptake in the stomach, an indication of deiodination, than [125I]m-IPQ. Moreover, [125I]PHY showed high uptake and prolonged retention in tumors and low accumulation in blood and muscle tissue resulting in a good tumor-to-blood ratio (0.94-1.50) and tumor-to-muscle ratio (1.02-1.95). The EGFR-TK selectivity of [125I]PHY was confirmed by pretreatment experiments with specific EGFR-TK inhibitors. New radioiodinated quinazoline derivatives were synthesized, which were found to have improved in vivo stability. In particular, [125I]PHY showed higher tumor accumulation than the other ligands which was indicative of selective binding to EGFR-TK. These desirable characteristics for [125I]PHY suggest that the 123I-labeled counterpart, [123I]PHY, could be a possible candidate for cancer diagnosis radiopharmaceutical. (author)