Trifluridine (TFT), floxuridine (FUDR) and 5-fluorouracil (5-FU) are nucleic acid-derived anticancer agents that disrupt DNA synthesis pathways. However, their effectiveness is difficult to predict due to inter-individual differences in nucleic acid metabolism. The intrinsic presence of fluorine in these compounds creates an opportunity to probe their pharmacokinetic properties using positron emission tomography (PET). Using an automated 18F-trifluoromethylation procedure, we have developed the first radiosynthesis of [18F]TFT. Furthermore, we present an alternative route to non-radioactive TFT from an iodinated nucleoside precursor. Biodistribution and PET-imaging data were obtained using a HCT116 xenograft model in mice, and the tumors were clearly identifiable 60 minutes post-injection. In vivo metabolite analysis of selected tissues revealed the presence of parent [18F]TFT, together with known [18F]TFT metabolites. Our preliminary data also suggest that uracil and uridine precursors that are iodinated at the 5-position can be 18F-fluorinated using [18F]fluoride; subsequently we have used this method to radiolabel [18F]FUDR and 5-[18F]FU analogues. An investigation is underway to elucidate the reaction mechanism. In a clinical setting, [18F]TFT, [18F]FUDR and 5-[18F]FU may provide useful predictions of treatment response for the development of personalized treatment plans. We present improved methods to access these radiotracers, enabling more thorough research into their role as PET imaging agents. Figure 1. Radiolabeled derivatives of TFT, FUDR and 5-FU.

Synthesis and evaluation of 18F-radiolabeled anticancer agents as tracers of nucleic acid metabolism

256th National Meeting (2018)

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