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

Hirata M, Kanai Y, Naka S, Yoshimoto M, Kagawa S, Matsumuro K, Katsuma H, Yamaguchi H, Magata Y, Ohmomo Y - Ann Nucl Med (2013)

Bottom Line: Six quinazoline derivatives were designed and synthesized, and among these, 6a-d were found to have relatively high EGFR-TK inhibitory potency.In contrast, [(125)I]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 [(125)I]PYK was confirmed by pretreatment experiments with specific EGFR-TK inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Osaka, Takatsuki 569-1094, Japan.

ABSTRACT

Objective: 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.

Methods: 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 (125)I-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.

Results: 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, [(125)I]6a ([(125)I]PYK) was found to have the highest tumor uptake and longest retention in tumors. In contrast, [(125)I]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 [(125)I]PYK was confirmed by pretreatment experiments with specific EGFR-TK inhibitors. Furthermore, [(125)I]PYK provided clear SPECT images of tumors.

Conclusions: Radioiodinated PYK, one of the newly synthesized quinazoline derivatives, was found to be a desirable ligand for EGFR-TK SPECT imaging. [(125)I]PYK showed high tumor accumulation and selective EGFR-TK binding and also succeeded in delivering high contrast imaging of tumors. These favorable characteristics of [(125)I]PYK suggest that the (123)I-labeled counterpart, [(123)I]PYK, would have great potential for diagnostic SPECT tumor imaging.

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Blocking effect of various inhibitors on [125I]PYK binding to EGFR-TK. Data represent mean ± SD, n = 3 *p < 0.01, **p < 0.001
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Fig4: Blocking effect of various inhibitors on [125I]PYK binding to EGFR-TK. Data represent mean ± SD, n = 3 *p < 0.01, **p < 0.001

Mentions: An in vitro pharmacological blocking study was performed to examine the degree of specific binding of [125I] PYK using A431 tumor cell membranes. As shown in Fig. 4, a significant reduction of [125I]PYK binding to EGFR-TK was found after pretreatment with EGFR-TK inhibitors such as m-IPQ, PD153035, and ZD1839. With genistein or RG13022 pretreatment, [125I]PYK binding was slightly decreased. The reduced radioactivity measured after treatment with these inhibitors correlated with the avidity of EGFR-TK. On the other hand, non-EGFR-TK inhibitors, such as AG17 (PDGFR-TK), HNMPA (IGFR-TK) and VEGFR inhibitor I (vascular endothelial growth factor tyrosine kinase), failed to block [125I]PYK binding to EGFR-TK. The difference between non-treatment and pretreatment data was examined by Student’s paired t test.Fig. 4


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

Hirata M, Kanai Y, Naka S, Yoshimoto M, Kagawa S, Matsumuro K, Katsuma H, Yamaguchi H, Magata Y, Ohmomo Y - Ann Nucl Med (2013)

Blocking effect of various inhibitors on [125I]PYK binding to EGFR-TK. Data represent mean ± SD, n = 3 *p < 0.01, **p < 0.001
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672506&req=5

Fig4: Blocking effect of various inhibitors on [125I]PYK binding to EGFR-TK. Data represent mean ± SD, n = 3 *p < 0.01, **p < 0.001
Mentions: An in vitro pharmacological blocking study was performed to examine the degree of specific binding of [125I] PYK using A431 tumor cell membranes. As shown in Fig. 4, a significant reduction of [125I]PYK binding to EGFR-TK was found after pretreatment with EGFR-TK inhibitors such as m-IPQ, PD153035, and ZD1839. With genistein or RG13022 pretreatment, [125I]PYK binding was slightly decreased. The reduced radioactivity measured after treatment with these inhibitors correlated with the avidity of EGFR-TK. On the other hand, non-EGFR-TK inhibitors, such as AG17 (PDGFR-TK), HNMPA (IGFR-TK) and VEGFR inhibitor I (vascular endothelial growth factor tyrosine kinase), failed to block [125I]PYK binding to EGFR-TK. The difference between non-treatment and pretreatment data was examined by Student’s paired t test.Fig. 4

Bottom Line: Six quinazoline derivatives were designed and synthesized, and among these, 6a-d were found to have relatively high EGFR-TK inhibitory potency.In contrast, [(125)I]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 [(125)I]PYK was confirmed by pretreatment experiments with specific EGFR-TK inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Osaka, Takatsuki 569-1094, Japan.

ABSTRACT

Objective: 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.

Methods: 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 (125)I-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.

Results: 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, [(125)I]6a ([(125)I]PYK) was found to have the highest tumor uptake and longest retention in tumors. In contrast, [(125)I]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 [(125)I]PYK was confirmed by pretreatment experiments with specific EGFR-TK inhibitors. Furthermore, [(125)I]PYK provided clear SPECT images of tumors.

Conclusions: Radioiodinated PYK, one of the newly synthesized quinazoline derivatives, was found to be a desirable ligand for EGFR-TK SPECT imaging. [(125)I]PYK showed high tumor accumulation and selective EGFR-TK binding and also succeeded in delivering high contrast imaging of tumors. These favorable characteristics of [(125)I]PYK suggest that the (123)I-labeled counterpart, [(123)I]PYK, would have great potential for diagnostic SPECT tumor imaging.

Show MeSH
Related in: MedlinePlus