Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Japan.
Mol Imaging Biol. 2010 Apr;12(2):181-91. doi: 10.1007/s11307-009-0265-5. Epub 2009 Sep 26.
Gefitinib (N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine, Iressa) is an approved anticancer drug. In this study, we labeled gefitinib with carbon-11 and evaluated [(11)C]gefitinib to explore its specific binding in intact fibrosarcoma (NFSa)-bearing mice.
[(11)C]Gefitinib was synthesized by the reaction of desmethyl precursor (1) with [(11)C]CH(3)I. In vitro uptake of [(11)C]gefitinib into NFSa, human-A431 epidermoid carcinoma, and Jurkat T cells was determined. Positron emission tomography (PET) imaging using [(11)C]gefitinib was performed for NFSa-bearing mice.
[(11)C]Gefitinib accumulated into NFSa cells with 2.1 uptake ratio (UR)/mg protein in cells. Addition of nonradioactive gefitinib decreased uptake in a concentration-dependent manner. [(11)C]Gefitinib also had high uptake (2.6 UR/mg protein) into epidermal growth factor receptor/tyrosine kinase (EGFR/TK)-rich A431 cells but low uptake (0.2 UR/mg protein) into EGFR/TK-poor Jurkat cells. In vivo distribution study on NFSa-bearing mice by the dissection method revealed that [(11)C]gefitinib specifically accumulated into the tumor. The ratio of radioactivity in tumors to that in blood and muscle as two comparative regions increased from 0.4 to 6.0 and from 0.6 to 5.0 during this experiment (0-60 min), respectively. PET for NFSa-bearing mice produced a clear tumor image, although high radioactivity was distributed throughout the body. Treatment with nonradioactive gefitinib (100 mg/kg) decreased uptake in the tumor. In vivo metabolite analysis demonstrated that [(11)C]gefitinib was stable in the tumor, liver, kidney, and blood.
These results demonstrated the promising potential of [(11)C]gefitinib to serve as a PET ligand for in vivo imaging of NFSa-bearing mice.
吉非替尼（N-（3-氯-4-氟苯基）-7-甲氧基-6-[3-（吗啉-4-基）丙氧基]喹唑啉-4-胺，易瑞沙）是一种已批准的抗癌药物。在这项研究中，我们用碳-11 标记吉非替尼，并评估 [(11)C]吉非替尼以探索其在完整纤维肉瘤（NFSa）荷瘤小鼠中的特异性结合。
通过将去甲基前体（1）与 [(11)C]CH(3)I 反应合成 [(11)C]吉非替尼。测定 [(11)C]吉非替尼在 NFSa、人 A431 表皮样癌细胞和 Jurkat T 细胞中的摄取。对 NFSa 荷瘤小鼠进行 [(11)C]吉非替尼的正电子发射断层扫描（PET）成像。
[(11)C]吉非替尼在 NFSa 细胞中的摄取率为 2.1 UR/mg 蛋白。非放射性吉非替尼的加入以浓度依赖性方式降低摄取。[(11)C]吉非替尼也对表皮生长因子受体/酪氨酸激酶（EGFR/TK）丰富的 A431 细胞具有高摄取（2.6 UR/mg 蛋白），而对 EGFR/TK 缺乏的 Jurkat 细胞摄取较低（0.2 UR/mg 蛋白）。通过解剖法对 NFSa 荷瘤小鼠的体内分布研究表明，[(11)C]吉非替尼特异性地积聚在肿瘤中。在实验过程中（0-60 分钟），肿瘤中放射性与血液和肌肉两个比较区域中的放射性的比值从 0.4 增加到 6.0，从 0.6 增加到 5.0。对 NFSa 荷瘤小鼠进行 PET 成像产生了清晰的肿瘤图像，尽管全身分布有高放射性。用非放射性吉非替尼（100 mg/kg）处理可降低肿瘤中的摄取。体内代谢物分析表明，[(11)C]吉非替尼在肿瘤、肝脏、肾脏和血液中稳定。
这些结果表明 [(11)C]吉非替尼有潜力成为用于 NFSa 荷瘤小鼠体内成像的 PET 配体。
