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

We prepared N(3)-(2-[(18)F]fluoroethyl)-thymidine ([(18)F]NFT202) and examined its potential as a positron emission tomography (PET) ligand for imaging cellular proliferation. [(18)F]NFT202 was synthesized from 3',5'-di-O-toluoyl-N(3)-(2-p-toluenesulfoxyethyl)-thymidine in a two-step reaction. N(3)-(2-fluoroethyl)-[2-(14)C]thymidine ([(14)C]NFT202) was also synthesized from [2-(14)C]thymidine in a one-step reaction. Whereas [(18)F]NFT202 did not accumulate in mouse Lewis lung carcinoma tumors, 3'-[(18)F]3'-fluoro-3'-deoxythymidine ([(18)F]FLT) showed significantly high uptake. To clarify this unexpected result, we evaluated the cell uptake of [(14)C]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 [(14)C]NFT202 was lower than that of [2-(14)C]3'-fluoro-3'-deoxythymidine. [(14)C]NFT202 was not effectively incorporated into the DNA fraction and was indeed washed out from tumor cells. These results clearly showed that [(18)F]NFT202 did not surpass the performance of [(18)F]FLT. We therefore conclude that [(18)F]NFT202 is not a suitable PET ligand for imaging tumor cell proliferation.