Radiolabeled 2′-fluorodeoxyuracil-β-D-arabinofuranoside (FAU) and 2′-fluoro-5-methyldeoxyuracil-β-D-arabinofuranoside (FMAU) as tumor-imaging agents in mice

Purpose: The purpose of the present study was to evaluate, in conjunction with the National Cancer Institute, the feasibility of using two thymidine analogs, 2'-fluorodeoxyuracil-beta-D-arabinofuranoside (FAU, NSC-678515) and 2'-fluoro-5-methyldeoxyuracil-beta-D-arabinofuranoside (FMAU, NSC-678516), as 18-fluorine-labeled positron emission tomography (PET) imaging agents. Methods: The in vivo distribution and DNA incorporation of [2-C-14]FAU, [2-C-14]FMAU, and [2(-14)C] thymidine (as a control) were studied in SCID mice bearing human xenografts of T-cell leukemia CCRF-CEM. Levels of drug-associated radioactivity in blood, tumor and normal tissues including liver, kidneys, heart, lungs, spleen, brain, and skeletal muscle were determined. Results: At 1 h after dosing, radioactivity from all three compounds was distributed in a generally nonspecific manner, except that spleen and tumor tissue had relatively high concentrations of radioactivity from [C-14] thymidine. At 4 h after dosing, the concentrations of radioactivity from [C-14]thymidine and [C-14]FMAU were relatively high in spleen and tumor tissue, and that from [C-14]FAU was highest in tumor tissue. The tumor/skeletal muscle concentration ratios were 2.25 +/- 0.69 and 3.07 +/- 0.42 for [C-14]FAU and [C-14]FMAU, respectively. At 24 h after dosing, only spleen and tumor tissues contained appreciable amounts of radioactivity from either compound. In tumor tissue, the levels of radioactivity from [C-14]FMAU were two- to threefold greater than those from [C-14] thymidine or [C-14]FAU. Examination of purified genomic DNA from tumor, liver, kidneys, brain, and skeletal muscle showed that, at 24 h after dosing, only DNA from tumor tissue contained appreciable concentrations of radioactivity. Radioactivity from [14C]FMAU in tumor DNA was 45% greater than that from [C-14] thymidine and about threefold greater than that from [C-14]FAU. Conclusions: The extent of accumulation of [C-14]FMAU in tumor tissue and incorporation into tumor DNA indicate that[F-18]FMAU could be useful as a functional PET tumor imaging agent.