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.
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Alkyl-fluorinated thymidine derivatives for imaging cell proliferation II. Synthesis and evaluation of N3-(2-[18F]fluoroethyl)-thymidine.
Nucl Med Biol
August 2006
Probe Research Section, Department of Molecular Probe, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
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.
View Article and Find Full Text PDFAlkyl-fluorinated thymidine derivatives for imaging cell proliferation I. The in vitro evaluation of some alkyl-fluorinated thymidine derivatives.
Nucl Med Biol
August 2006
Probe Research Section, Department of Molecular Probe, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Derivatives of 2'-deoxyuridine that contain fluoroalkyl groups at the C5 position and derivatives of thymidine that contain fluoroalkyl groups at the N3 position were synthesized and examined in three in vitro assays designed to evaluate their potential as radiopharmaceuticals for imaging cellular proliferation. Three of the former nucleosides and five of the latter were synthesized. The three assays were as follows: (a) phosphoryl transfer assay, which showed that all three of the former nucleosides and four of the latter ones were phosphorylated by recombinant human thymidine kinase 1 (TK1) and that N(3)-(2-fluoroethyl)-thymidine (NFT202) was the most potent substrate of the eight nucleosides studied; (b) transport assay, which indicated that all eight nucleosides had good affinity for an 6-[(4-nitrobenzyl)thio]-9-beta-d-ribofuranosylpurine-sensitive mouse erythrocyte nucleoside transporter, with inhibition constants in the range of 0.
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