A useful EGFR-TK ligand for tumor diagnosis with SPECT: development of radioiodinated 6-(3-morpholinopropoxy)-7-ethoxy-4-(3'-iodophenoxy)quinazoline.
A useful EGFR-TK ligand for tumor diagnosis with SPECT: development of radioiodinated 6-(3-morpholinopropoxy)-7-ethoxy-4-(3'-iodophenoxy)quinazoline.
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DOI：
10.1007/s12149-013-0703-y
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发表时间：
2013-06
影响因子：
2.6
通讯作者：
Ohmomo, Yoshiro
中科院分区：
文献类型：
--
作者：
Hirata, Masahiko;Kanai, Yasukazu;Naka, Sadahiro;Yoshimoto, Mitsuyoshi;Kagawa, Shinya;Matsumuro, Keiji;Katsuma, Hideyuki;Yamaguchi, Hiroshi;Magata, Yasuhiro;Ohmomo, Yoshiro
表皮生长因子受体酪氨酸激酶（EGFR-TK）是肿瘤诊断的一个重要靶点。以前，放射性碘标记的4-（3-碘苯氧基）-6，7-二乙氧基喹唑啉（PHY）被报道具有作为肿瘤显像剂的良好特性。我们已经探索了开发上级放射性碘标记PHY的肿瘤诊断配体的可行性。设计了新型苯氧基喹唑啉衍生物，在PHY的6位引入了不同的侧链。评价了新衍生物中断EGFR-TK磷酸化的IC 50值，并与已知的EGFR-TK抑制剂进行了比较。用A431荷瘤小鼠进行了新的125 I标记衍生物的肿瘤摄取研究。通过体外阻断研究和结合试验分析选择性和结合特征。此外，使用A431荷瘤小鼠进行SPECT/CT扫描。设计并合成了6个喹唑啉衍生物，其中6a-d具有较强的EGFR-TK抑制活性。在肿瘤摄取研究中，发现[125 I]6a（[125 I]PYK）具有最高的肿瘤摄取和在肿瘤中最长的保留。相比之下，[125 I]PYK从外周组织中迅速清除，导致注射后24小时的高肿瘤-组织比。此外，[125 I]PYK的EGFR-TK选择性通过使用特异性EGFR-TK抑制剂的预处理实验来证实。此外，[125 I]PYK提供了清晰的肿瘤SPECT图像。放射性碘标记的PYK是一种新合成的喹唑啉衍生物，是EGFR-TK SPECT显像的理想配体。[125 I]PYK显示高肿瘤蓄积和选择性EGFR-TK结合，并且还成功地提供肿瘤的高对比度成像。[125 I]PYK的这些有利特性表明，123 I标记的对应物[123 I]PYK将具有诊断SPECT肿瘤成像的巨大潜力。
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. New phenoxyquinazoline derivatives were designed with various side chains introduced to the 6th position of PHY. The IC50 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 125I-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. 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, [125I]6a ([125I]PYK) was found to have the highest tumor uptake and longest retention in tumors. In contrast, [125I]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 [125I]PYK was confirmed by pretreatment experiments with specific EGFR-TK inhibitors. Furthermore, [125I]PYK provided clear SPECT images of tumors. Radioiodinated PYK, one of the newly synthesized quinazoline derivatives, was found to be a desirable ligand for EGFR-TK SPECT imaging. [125I]PYK showed high tumor accumulation and selective EGFR-TK binding and also succeeded in delivering high contrast imaging of tumors. These favorable characteristics of [125I]PYK suggest that the 123I-labeled counterpart, [123I]PYK, would have great potential for diagnostic SPECT tumor imaging.
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影响因子：
3.1
作者：
Mishani, E;Abourbeh, G;Shaul, M
通讯作者：
Shaul, M
DOI：
10.1039/jr9490001354
发表时间：
1949-01-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY
影响因子：
--
作者：
MORLEY, JS;SIMPSON, JCE
通讯作者：
SIMPSON, JCE
影响因子：
1.8
作者：
Seimbille, Y;Czernin, J;Silverman, DHS
通讯作者：
Silverman, DHS
影响因子：
8.8
作者：
McLeod, H L;Brunton, V G;Eckardt, N;Lear, M J;Robins, D J;Workman, P;Graham, M A
通讯作者：
Graham, M A
影响因子：
56.9
作者：
FRY, DW;KRAKER, AJ;BRIDGES, AJ
通讯作者：
BRIDGES, AJ