A useful EGFR-TK ligand for tumor diagnosis with SPECT: development of radioiodinated 6-(3-morpholinopropoxy)-7-ethoxy-4-(3 %26apos;-iodophenoxy)quinazoline

作者：Hirata Masahiko; Kanai Yasukazu; Naka Sadahiro; Yoshimoto Mitsuyoshi; Kagawa Shinya; Matsumuro Keiji; Katsuma Hideyuki; Yamaguchi Hiroshi; Magata Yasuhiro; Ohmomo Yoshiro^*

来源：Annals of Nuclear Medicine, 2013, 27(5): 431-443.

DOI：10.1007/s12149-013-0703-y

• EGF
• Radiopharmaceutical
• SPECT
• Tyrosine kinase
• Quinazoline
• Radioiodine

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. %26lt;br%26gt;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 I-125-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. %26lt;br%26gt;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, [I-125]6a ([I-125]PYK) was found to have the highest tumor uptake and longest retention in tumors. In contrast, [I-125]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 [I-125]PYK was confirmed by pretreatment experiments with specific EGFR-TK inhibitors. Furthermore, [I-125]PYK provided clear SPECT images of tumors. %26lt;br%26gt;Radioiodinated PYK, one of the newly synthesized quinazoline derivatives, was found to be a desirable ligand for EGFR-TK SPECT imaging. [I-125]PYK showed high tumor accumulation and selective EGFR-TK binding and also succeeded in delivering high contrast imaging of tumors. These favorable characteristics of [I-125]PYK suggest that the I-123-labeled counterpart, [I-123]PYK, would have great potential for diagnostic SPECT tumor imaging.

• 出版日期2013-6