[C-11]Gefitinib ([C-11]Iressa): Radiosynthesis, In Vitro Uptake, and In Vivo Imaging of Intact Murine Fibrosarcoma

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 [C-11]gefitinib to explore its specific binding in intact fibrosarcoma (NFSa)-bearing mice. [C-11]Gefitinib was synthesized by the reaction of desmethyl precursor (1) with [C-11]CH3I. In vitro uptake of [C-11]gefitinib into NFSa, human-A431 epidermoid carcinoma, and Jurkat T cells was determined. Positron emission tomography (PET) imaging using [C-11]gefitinib was performed for NFSa-bearing mice. [C-11]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. [C-11]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 [C-11]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 [C-11]gefitinib was stable in the tumor, liver, kidney, and blood. These results demonstrated the promising potential of [C-11]gefitinib to serve as a PET ligand for in vivo imaging of NFSa-bearing mice.