Abstract
ObjectiveEpidermal 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.MethodsNew 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.ResultsSix 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.ConclusionsRadioiodinated 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.
Highlights
Epidermal growth factor receptor (EGFR) plays a key role in signal transduction pathways that regulate fundamentally important cellular functions
We have explored the feasibility of developing tumor diagnosis ligands superior to radioiodinated PHY
Epidermal growth factor receptor tyrosine kinase (EGFR-TK) phosphorylation is stimulated by epidermal growth factor (EGF) or transforming growth factor a (TGFa) binding to the extracellular ligand-binding domain of EGFR and subsequent receptor dimerization
Summary
Epidermal growth factor receptor (EGFR) plays a key role in signal transduction pathways that regulate fundamentally important cellular functions. EGFR-TK phosphorylation is stimulated by epidermal growth factor (EGF) or transforming growth factor a (TGFa) binding to the extracellular ligand-binding domain of EGFR and subsequent receptor dimerization. EGFR-TK represents an attractive target for the development of new antitumor agents [7, 8]. In an effort to develop new cancer diagnostic agents, several PET and SPECT ligands have been synthesized and evaluated for imaging of EGFR-TK. The feasibility of targeting EGFR for tumor imaging has been experimentally demonstrated using 18F or 11C-labeled EGFR-TK inhibitors [14,15,16,17,18,19,20]; these labeled compounds were observed to produce high radioactivity in the blood and peripheral tissues. Tumor images with these radioligands were affected by the radioactivity in peripheral tissues a short time after injection
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