当前位置： SCI文献检索 > ANNALS OF NUCLEAR MEDICINE期刊下所有文献 > Synthesis and evaluation of radioiodinated phenoxyquinazoline and benzylaminoquinazoline derivatives as new EGF receptor tyrosine kinase imaging ligands for tumor diagnosis using SPECT.

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

Abstract：

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 ([(125)I]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 [(125)I]PHY and [(125)I]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 [(125)I]PHY and [(125)I]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 [(125)I]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: IC50 = 12.7 ± 7.2 nM, BAY: IC50 = 51.0 ± 8.9 nM). [(125)I]PHY and [(125)I]BAY were conveniently synthesized from tributylstannyl precursors. In in vivo biodistribution studies, [(125)I]PHY and [(125)I]BAY were observed to have lower uptake in the stomach, an indication of deiodination, than [(125)I]m-IPQ. Moreover, [(125)I]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 [(125)I]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, [(125)I]PHY showed higher tumor accumulation than the other ligands which was indicative of selective binding to EGFR-TK. These desirable characteristics for [(125)I]PHY suggest that the (123)I-labeled counterpart, [(123)I]PHY, could be a possible candidate for cancer diagnosis radiopharmaceutical.

journal_name

Ann Nucl Med

journal_title

Annals of nuclear medicine

authors

Hirata M,Kanai Y,Naka S,Matsumuro K,Kagawa S,Yoshimoto M,Ohmomo Y

doi

10.1007/s12149-012-0583-6

subject

Has Abstract

pub_date

2012-06-01 00:00:00

pages

381-9

issue

eissn

0914-7187

issn

1864-6433

journal_volume

pub_type

杂志文章

在线工具

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