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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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Tumor-to-organ ratios of [125I]PYK in A431 tumor-bearing mice a: tumor to blood (open circle), tumor to muscle (open triangle) b: tumor to lung (closed circle), tumor to kidney (closed triangle), tumor to liver (closed square)
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Fig3: Tumor-to-organ ratios of [125I]PYK in A431 tumor-bearing mice a: tumor to blood (open circle), tumor to muscle (open triangle) b: tumor to lung (closed circle), tumor to kidney (closed triangle), tumor to liver (closed square)

Mentions: Moreover, biodistribution studies of [125I]PYK were performed in A431 tumor-bearing mice with time points 1, 6, 12, and 24 h after intravenous administration. The results are summarized in Table 4. The accumulation of [125I]PYK in the tumor was high, and the tumor radioactivity level gradually decreased to 1.53 ± 0.15 % ID/g tissue from 1 to 24 h after imaging agent injection. In contrast with the high tumor uptake and retention of [125I]PYK, accumulation in the blood and muscle was low, which resulted in good tumor/blood (57.0, Fig. 3a) and tumor/muscle (45.5, Fig. 3a) ratios 24 h after injection. [125I]PYK also was found to have a relatively high uptake into the lungs, liver, and kidneys 1 h after injection; however, clearance of [125I]PYK from these organs was more rapid than from tumor tissue. In particular, the radioactivity accumulated in the liver 24 h after injection was approximately 1/50 of the radioactivity 1 h after injection. Thus, tumor-to-organ ratios for [125I]PYK 24 h after injection had desirable values (Fig. 3b: tumor to lung: 8.5, tumor to kidney: 4.3, tumor to liver: 3.0) for tumor diagnostic imaging.Table 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)

Tumor-to-organ ratios of [125I]PYK in A431 tumor-bearing mice a: tumor to blood (open circle), tumor to muscle (open triangle) b: tumor to lung (closed circle), tumor to kidney (closed triangle), tumor to liver (closed square)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Tumor-to-organ ratios of [125I]PYK in A431 tumor-bearing mice a: tumor to blood (open circle), tumor to muscle (open triangle) b: tumor to lung (closed circle), tumor to kidney (closed triangle), tumor to liver (closed square)
Mentions: Moreover, biodistribution studies of [125I]PYK were performed in A431 tumor-bearing mice with time points 1, 6, 12, and 24 h after intravenous administration. The results are summarized in Table 4. The accumulation of [125I]PYK in the tumor was high, and the tumor radioactivity level gradually decreased to 1.53 ± 0.15 % ID/g tissue from 1 to 24 h after imaging agent injection. In contrast with the high tumor uptake and retention of [125I]PYK, accumulation in the blood and muscle was low, which resulted in good tumor/blood (57.0, Fig. 3a) and tumor/muscle (45.5, Fig. 3a) ratios 24 h after injection. [125I]PYK also was found to have a relatively high uptake into the lungs, liver, and kidneys 1 h after injection; however, clearance of [125I]PYK from these organs was more rapid than from tumor tissue. In particular, the radioactivity accumulated in the liver 24 h after injection was approximately 1/50 of the radioactivity 1 h after injection. Thus, tumor-to-organ ratios for [125I]PYK 24 h after injection had desirable values (Fig. 3b: tumor to lung: 8.5, tumor to kidney: 4.3, tumor to liver: 3.0) for tumor diagnostic imaging.Table 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