Article Figures & Data
Figures
- FIGURE 1.
Paired nucleoside accumulation studies in RG2TK+ transduced cells. (A) 18F-FHBG-14C-FIAU (⊞) and 18F-FHPG-14C-FIAU (○) accumulation data (mL medium/g cells) are shown. (B) 18F-FHBG-14C-FIAU and 18F-FHPG-14C-FIAU comparisons with 3H-TdR are shown: 14C-FIAU (•), 18F-FHBG (⊞), and 18F-FHPG (□). Each point represents paired comparison of uptake results obtained from single triple-label experiment; experimental times varied between 10 and 180 min.
- FIGURE 2.
Paired PET imaging studies comparing 124I-FIAU and 18F-FHBG or 18F-FHPG were performed. Coronal (A) and axial (B) PET images are shown for 3 different rats. Each animal had 2 imaging studies within 24 h, and comparable image pairs are shown in each quadrant of A and B. Location of RG2TK+ xenograft is indicated by arrow. Linear scaling of image intensity was performed to achieve similar background intensity on all images; background radioactivity in thorax was 0.013 and 0.027 %dose/g for animal 1, 0.024 and 0.18 %dose/g for animal 2, and 0.23 and 0.24 %dose/g for animal 3 (FHBG or FHPG and FIAU, respectively). No radioactivity above background is visualized in control RG2 xenograft. Several tissues had substantially higher values than indicated on intensity scale. For example, FIAU levels in RG2TK+ xenografts in animals 1–3 were 0.55, 1.7, and 1.2 %dose/g, respectively. Also note high values of radioactivity in stomach (6.0 %dose/g) and bladder (3.9 %dose/g) in 2-h study (animal 2). FHBG levels in abdominal viscera (2.8–3.2 %dose/g) and bladder (11 and 80 %dose/g) were also substantial at 2 h (animals 1 and 2); similar values were measured for FHPG in abdomen (3.4 %dose/g) and bladder (63 %dose/g) of animal 3. Note that FIAU bladder radioactivity had essentially cleared by 24 h (animals 1 and 3).
- FIGURE 3.
Comparison of 10-min imaging frames of FIAU accumulation. Ten-minute coronal image frames through RG2TK+ and RG2 xenografts are shown at various times after intravenous injection of 124I-FIAU. Image intensity scale is same for all frames.
- FIGURE 4.
Radioactivity-time profiles in RG2TK+ and RG2 xenografts after intravenous injection of 124I-FIAU, 18F-FHBG, and 18F-FHPG. Values (%dose/mL) are the mean ± SD (n = 6) of maximum pixel value measured in each xenograft. FHBG and FIAU data were obtained from same set of animals imaged on consecutive days.
- FIGURE 5.
Chemical structures of pyrimidine (A) and acycloguanosine (B) nucleoside probes. IUdR = 2′-deoxy-5-iodo-1-β-d-ribofuranosyl-uracil; BrUdR = 2′-deoxy-5-bromo-1-β-d-ribofuranosyl-uracil.
Tables
Tissue FIAU, 2 h FHBG, 2 h* FHPG, 2 h* FIAU, 24 h† Mean ± SD n Mean ± SD n Mean ± SD n Mean ± SD n RG2TK+ 1.217 ± 0.170 12 0.074‡ ± 0.049 6 0.023‡ ± 0.008 6 1.527§ ± 0.399 11 RG2 0.112 ± 0.042 12 0.013¶ ± 0.006 6 0.018¶ ± 0.005 6 0.026‡ ± 0.015 11 Plasma 0.244 ± 0.071 12 0.010¶ ± 0.003 6 0.043¶ ± 0.032 6 0.062‡ ± 0.035 11 Muscle 0.070 ± 0.015 12 0.016¶ ± 0.007 6 0.039‖ ± 0.025 6 0.015‡ ± 0.010 11 Liver 0.083 ± 0.028 12 0.026¶ ± 0.012 6 0.038¶ ± 0.020 6 0.018‡ ± 0.009 5 Stomach 0.137 ± 0.040 12 0.014¶ ± 0.004 6 0.016¶ ± 0.007 6 0.210§ ± 0.123 5 Heart 0.073 ± 0.017 12 0.006¶ ± 0.003 6 0.012‡ ± 0.004 6 0.011‡ ± 0.007 5 Lung 0.165 ± 0.045 12 0.013¶ ± 0.008 6 0.019‡ ± 0.005 6 0.028‡ ± 0.018 5 Kidney 0.249 ± 0.124 11 0.052‖ ± 0.061 6 0.079‖ ± 0.025 5 0.026‡ ± 0.018 5 Small intestine 0.170 ± 0.035 12 0.038¶ ± 0.025 6 0.029¶ ± 0.025 6 0.076‡ ± 0.026 5 Large intestine 0.170 ± 0.029 12 0.052¶ ± 0.027 6 0.035¶ ± 0.024 6 0.056‡ ± 0.014 5 Thyroid 0.125 ± 0.039 12 0.010¶ ± 0.004 6 0.016¶ ± 0.004 6 0.022‡ ± 0.014 5 Spleen 0.145 ± 0.047 12 0.021¶ ± 0.010 6 0.026‡ ± 0.009 6 0.027‡ ± 0.010 5 Brain 0.029 ± 0.007 12 0.0009¶ ± 0.0012 6 0.0027¶ ± 0.0012 6 0.0011‡ ± 0.0007 5 ↵* Comparison of FHBG or FHPG vs. FIAU at 2 h by paired t test.
↵† Comparison of FIAU at 24 h vs. 2 h by unpaired t test.
↵‡ P < 0.0001.
↵§ P = not significant.
↵¶ 0.0001 < P < 0.0015.
↵‖ 0.005 < P < 0.02.
Probability values are nominal significance levels for univariate tests unadjusted for multiple comparisons; P < 0.0001 and 0.0001 < P < 0.0015 remain significant even with conservative Bonferroni correction.
- TABLE 2
Paired Comparisons of Probe Accumulation in HSV1-tk Transduced and Wild-Type RG2 Xenografts
Measurement 2 h* 2 h* 24 h* FIAU FHBG FIAU FHPG FIAU Xenograft difference† (RG2TK+) − (RG2) 1.12 ± 0.16 0.062 ± 0.043 1.11 ± 0.19 0.006 ± 0.010 1.50 ± 0.69 Xenograft ratio‡ RG2TK+/RG2 11.3 ± 2.6 5.9 ± 2.3 8.9 ± 2.2 1.4 ± 0.7 65 ± 21 RG2TK+/muscle 18.1 ± 3.8 4.9 ± 2.2 16.9 ± 3.1 0.77 ± 0.44 124 ± 58 ↵* Paired comparison from same animal tissue sampling dataset.
↵† Background-corrected RG2TK+ value. Difference expressed as %dose/g tissue.
↵‡ Concentration ratio.
Paired 2-sample t tests of FIAU 2 h vs. FHBG 2 h or FIAU 2 h vs. FHPG 2 h for (RG2TK+) − (RG2), RG2TK+/RG2, RG2TK+/muscle: P < 0.0001. Unpaired, 2-sample t tests of FIAU 2 h vs. 24 h for RG2TK+/RG2, RG2TK+/muscle: P < 0.0001. Unpaired, 2-sample t tests of FIAU 2 h vs. 24 h for (RG2TK+) − (RG2): P = not significant.
Radiolabeled probe Chemical name References Pyrimidine derivatives FIAU (123I, 124I, 125I, 131I) 2′-Fluoro-2′-deoxy-1-β-d-arabinofuranosyl-5-iodouracil 1–7, 22–24 FIRU (125I) 2′-Fluoro-2′-deoxy-5-iodo-1-β-d-ribofuranosyl-uracil 22, 23 FMAU (11C) 2′-Fluoro-2′-deoxy-5-methyl-1-β-d-arabinofuranosyl-uracil 25, 26 IVFRU (123I, 125I, 131I) 2′-Fluoro-2′-deoxy-5-iodovinyl-1-β-d-ribofuranosyl-uracil 23, 27, 28 IUdR (3H) 2′-Deoxy-5-iodo-1-β-d-ribofuranosyl-uracil (iododeoxyuridine) 1 Acycloguanosine derivatives ACV (8-14C, 8-3H) 9-[(2-Hydroxy-1-ethoxy)methyl]guanine (acyclovir) 11, 24 GCV (8-14C, 8-3H) 9-[(2-Hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine (ganciclovir) 1, 10, 11 PCV (8-3H) 9-[4-Hydoxy-3-(hydoxymethyl)butyl]guanine (penciclovir) 14, 15 FGCV (8-18F) 8-Fluoro-9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine (fluoroganciclovir) 12, 13 FPCV (8-18F) 8-Fluoro-9-[4-hydoxy-3-(hydoxymethyl)butyl]guanine (fluoropenciclovir) 14, 15 FHPG (3-18F) 9-[3-Fluoro-1-hydoxy-2-propoxymethyl]guanine 16, 17, 24, 25 FHBG (4-18F) 9-[4-Fluoro-3-(hydoxymethyl)butyl]guanine 18, 19, 29 References relate primarily to probe comparisons; because of reference number limitation, complete listing of all references was not possible.
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