Alkyl-fluorinated thymidine derivatives for imaging cell proliferation: II. Synthesis and evaluation of N3-(2-[18F]fluoroethyl)-thymidine

We prepared N3-(2-[18F]fluoroethyl)-thymidine ([18F]NFT202) and examined its potential as a positron emission tomography (PET) ligand for imaging cellular proliferation. [18F]NFT202 was synthesized from 3′,5′-di-O-toluoyl-N3-(2-p-toluenesulfoxyethyl)-thymidine in a two-step reaction. N3-(2-fluoroethyl)-[2-14C]thymidine ([14C]NFT202) was also synthesized from [2-14C]thymidine in a one-step reaction. Whereas [18F]NFT202 did not accumulate in mouse Lewis lung carcinoma tumors, 3′-[18F]3′-fluoro-3′-deoxythymidine ([18F]FLT) showed significantly high uptake. To clarify this unexpected result, we evaluated the cell uptake of [14C]NFT202 in vitro. The uptake was approximately eight times higher in thymidine kinase 1 (TK1)+ clones (L-M cells) than in TK1-deficient mutant L-M(TK−) cells (P<.01, Student's t test). In addition, we observed a positive correlation between tracer uptake and the S-phase fraction. However, the net in vitro tumor cell uptake of [14C]NFT202 was lower than that of [2-14C]3′-fluoro-3′-deoxythymidine. [14C]NFT202 was not effectively incorporated into the DNA fraction and was indeed washed out from tumor cells. These results clearly showed that [18F]NFT202 did not surpass the performance of [18F]FLT. We therefore conclude that [18F]NFT202 is not a suitable PET ligand for imaging tumor cell proliferation.