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

Abstract.

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-β-D-arabinofuranoside (FAU, NSC-678515) and 2′-fluoro-5-methyldeoxyuracil-β-D-arabinofuranoside (FMAU, NSC-678516), as 18-fluorine-labeled positron emission tomography (PET) imaging agents. Methods: The in vivo distribution and DNA incorporation of [2-¹⁴C]FAU, [2-¹⁴C]FMAU, and [2-¹⁴C]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 [¹⁴C]thymidine. At 4 h after dosing, the concentrations of radioactivity from [¹⁴C]thymidine and [¹⁴C]FMAU were relatively high in spleen and tumor tissue, and that from [¹⁴C]FAU was highest in tumor tissue. The tumor/skeletal muscle concentration ratios were 2.25±0.69 and 3.07±0.42 for [¹⁴C]FAU and [¹⁴C]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 [¹⁴C]FMAU were two- to threefold greater than those from [¹⁴C]thymidine or [¹⁴C]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 [¹⁴C]thymidine and about threefold greater than that from [¹⁴C]FAU. Conclusions: The extent of accumulation of [¹⁴C]FMAU in tumor tissue and incorporation into tumor DNA indicate that [¹⁸F]FMAU could be useful as a functional PET tumor-imaging agent.