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Blocking Catabolism with Eniluracil Enhances PET Studies of 5-[¹⁸F]Fluorouracil Pharmacokinetics

Departments of Radiology and Biomedical Engineering, University of Southern California, Los Angeles, California; and Glaxo Wellcome, Inc., Research Triangle Park, North Carolina

View larger version (24K): [in this window] [in a new window]   FIGURE 1. Metabolism of FU. DPD = dihydropyrimidine dehydrogenase; FUH2 = dihydrofluorouracil; FUPA = -fluoro-ß-ureido-propanoic acid; FBAL = -fluoro-ß-alanine; BAL = ß-alanine; F– = fluoride ion; FdUrd = fluorodeoxyuridine; FUrd = fluorouridine; FdUMP, FdUDP, and FdUTP = fluorodeoxyuridine mono-, di-, and triphosphate, respectively; FUMP, FUDP, and FUTP = fluorouridine mono-, di-, and triphosphate, respectively; TS, thymidylate synthase; F-DNA and F-RNA = fluorinated DNA and RNA, respectively; CH2FH4 = 5,10-methylene tetrahydrofolate. (Note that "F" in CH2FH4 symbolizes folate, not fluorine (6). Chemical structures of FU and its metabolites can be found in (4) and (7).)

View larger version (36K): [in this window] [in a new window]   FIGURE 2. Effect of eniluracil (EU) on tumor visualization. Images are thin anteroposterior coronal and transaxial slices through tumors 110–120 min after intravenous injection of [18F]FU (FU). Spatial resolution of reconstructed images is 6–7 mm FWHM in the transaxial plane and 6 mm in the axial dimension. Tumor locations were verified by 18F marker images. Tumor weights and standardized uptake values (SUVs) were determined by direct measurements on excised tissues. (A) Tumors in legs (left [upper]: 1.3 g, SUV 1.05; right: 0.32 g, SUV 1.57) are clearly visualized relative to adjacent normal tissues. (B) Tumors (left: 0.22 g, SUV 0.61; right: 0.43 g, SUV 0.67) are less distinguishable, attributed in part to elevated bone uptake of 18F.

View larger version (43K): [in this window] [in a new window]   FIGURE 3. Analysis of 18F-labeled metabolites in arterial plasma. (A and B) Radiochromatograms obtained by isocratic-elution HPLC of acid-soluble extract from samples taken 90 min after intravenous injection of [18F]FU into a rat pretreated with eniluracil (A) and 60 min after intravenous injection of [18F]FU into a rat not pretreated with eniluracil (B). (C) UV absorbance chromatogram (wavelengths 254 nm) of an authentic sample of FU, which was obtained just before the radiochromatogram of (A). (D) UV absorbance chromatogram (wavelengths 214 nm) recorded simultaneously with radiochromatogram of (B). An aliquot of solution containing authentic, nonradiolabeled samples of -fluoro-ß-alanine (FBAL), dihydrofluorouracil (FUH2), FU, fluorouridine (FUrd), and fluorodeoxyuridine (FdUrd) was added to the injectate in the run depicted in (B and D). Radiochromatogram for 18F-labeled fluoride ion ([18F]F–) (dashed lines in D) was determined separately. Percentages of recovered radiolabel associated with various peaks are shown in (A and B).

View larger version (51K): [in this window] [in a new window]   FIGURE 4. Analysis of 18F-labeled metabolites in tumors. Shown are radiochromatograms (A and B) and corresponding UV chromatograms (C and D) obtained by gradient-elution HPLC of acid-soluble extract from Ward tumors. Tumors were harvested 2 h after intravenous injection of [18F]FU from rats pretreated with eniluracil (A and C) and not pretreated with eniluracil (B and D). UV absorption was measured for wavelengths 214 nm. Percentages of radiolabel in each peak, as well as in the AIF, are indicated in (A and B). Aliquots of solutions containing authentic, nonradiolabeled samples of compounds indicated in the UV chromatograms were added to tumor extracts before injection for HPLC. FUrd = fluorouridine; FdUrd = fluorodeoxy-uridine; FUMP, FUDP, and FUTP = fluorouridine mono-, di-, and triphosphate, respectively; FdUMP, FdUDP, and FdUTP = fluorodeoxyuridine mono-, di-, and triphosphate, respectively; AIF = acid-insoluble fraction; FBAL = -fluoro-ß-alanine; FUPA = -fluoro-ß-ureido-propanoic acid; UDP = uridine diphosphate; UTP = uridine triphosphate; F– = fluoride ion. Standard chromatogram for [18F]F– (dashed lines in D) was determined separately. There was no evidence of free [18F]F– in studies shown.

View larger version (38K): [in this window] [in a new window]   FIGURE 5. Effect of eniluracil (EU) on tissue distribution of radiolabel from [18F]FU (FU) at 2 h after injection. For tumor SUVs, n = 4 for FU-only; n = 12 for FU + EU. For tumor-to-normal tissue ratios, n = 2 for FU-only; n = 5 for FU + EU. Error bars indicate SEMs. *P < 0.05; **P < 0.01. t = tumor; pl = plasma; msc = muscle; liv = liver; spl = spleen; kid = kidney; sm int = small intestine.

View larger version (40K): [in this window] [in a new window]   FIGURE 6. Effect of eniluracil (EU) on 18F time–activity curves in tissues, organs, and arterial plasma after intravenous injection of [18F]FU (FU). Tissue and organ time–activity curves (A–C; n = 4 and 2 for FU + EU and FU-only, respectively) were extracted from PET images, whereas plasma curves (D; n = 5 and 2 for FU + EU and FU-only, respectively) were obtained by direct arterial sampling. Tissue and organ data were normalized at the final time point to values obtained by ex vivo assay of excised tissue samples obtained after killing at 2 h. Data are expressed in terms of SUV. Note that ordinate scales differ in (A–D).

View larger version (30K): [in this window] [in a new window]   FIGURE 7. Effect of eniluracil (EU) on molecular distribution of radiolabel from FU in tumor at 2 h after injection. Data reflect percentages of recovered radioactivity. Data obtained with [18F]FU and [3H]FU were combined within each treatment group (i.e., eniluracil or placebo). Results with individual radiotracers are given in Table 3. n = 5 for FU-only; n = 8 for FU + EU. Error bars indicate SEMs. *P < 0.01; **P 0.05.