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

摘要

Objective: 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. Methods: 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. Results: The new derivatives were found to have high inhibitory potency against EGFR-TK (PHY: IC 50 = 12.7 ± 7.2 nM, BAY: IC 50 = 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. Conclusion: 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.