Alkyl-fluorinated thymidine derivatives for imaging cell proliferation:

Abstract 

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.

Keywords: Nucleosides, Positron emission tomography, Proliferation, [¹⁸F]NFT202