Comparative Evaluation of [18F]5-Fluoroaminosuberic Acid and (4S)-4-3-[18F]fluoropropyl)-l-Glutamate as System 
–Targeting Radiopharmaceuticals
Article Figures & Data
Figures
- FIGURE 1.
(A) [18F]FASu in vitro uptake at 20, 40, and 60 min in absence and presence of xCT inhibitor sulfasalazine (1 mM). (B) [18F]FSPG in vitro uptake at 20, 40, and 60 min in absence and presence of 1 mM sulfasalazine. Radiotracer structures are embedded into graphs. (C) [18F]FASu and [18F]FSPG in vitro uptake in presence of sulfasalazine (1 mM). Cells were incubated with tracer (red bars for [18F]FASu, black bars for [18F]FSPG) for 20, 40, or 60 min. Sulfasalazine was coadded with tracer. All uptake values are normalized to protein concentration and presented as percentage uptake per minute per milligram of protein (A and B) or as counts per minute per microgram of protein (C). SSZ = sulfasalazine. *P < 0.05. **P < 0.01. ***P < 0.001. ****P < 0.0001.
- FIGURE 2.
Two-way ANOVA analysis of 1-h uptake of [18F]FASu (A) and [18F]FSPG (B) in A549, U-87, and MDA-MB-231 cells, expressed as percentage of control sample uptake. BCH = 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. *P < 0.05. **P < 0.01. ***P < 0.001. ****P < 0.0001.
- FIGURE 3.
Dose-dependent competition cell uptake assays were performed in A549 (top) and MDA-MB-231 (bottom) cells using 148 kBq per well of either [18F]FASu (A) or [18F]FSPG (B) and increasing concentration of l-cystine or l-glutamate.
- FIGURE 4.
(A) Uptake of [18F]FSPG and [18F]FASu in A549 tumor–bearing mice at 1 h after injection with and without blocking reagent (100 mg/kg ASu). Arrows indicate location of A549 tumors on fused PET/CT maximum-intensity projection images. (B and C) Two-way ANOVA of tumor-to-muscle and tumor-to-lung ratios (C) and tumor and lung uptake (B) for [18F]FSPG and [18F]FASu in A549 tumor–bearing mice at 1 h after injection. P value varied for each comparison but was always >0.05. T = tumor.
- FIGURE 5.
Comparative study. (A) Uptake of [18F]FSPG and [18F]FASu in U-87 tumor–bearing mice at 1 h after injection. Arrows indicate location of U-87 tumors on fused PET/CT maximum-intensity projection images. (B and C) Two-way ANOVA of tumor-to-muscle and tumor-to brain ratios (C) and tumor and brain uptake (B) for [18F]FSPG and [18F]FASu in U-87 tumor–bearing mice at 1 h after injection. *P < 0.05. **P < 0.01. ****P < 0.0001.
Tables
- TABLE 1.
Half-Maximal Inhibitory Concentrations (μM) from Tracer Competition Uptake Assays Against l-Cystine and l-Glutamate
Substrate Cell line [18F]FASu (±SE) [18F]FSPG (±SE) l-Cystine A549 3.92 ± 0.60 3.23 ± 1.01 l-Glutamate A549 10.93 ± 1.00 5.20 ± 1.18 l-Cystine MDA-MB-231 4.56 ± 0.89 7.88 ± 1.36 l-Glutamate MDA-MB-231 41.01 ± 6.32 29.29 ± 3.60 Assays were performed in A549 and MDA-MB-231 cells (n = 3).
- TABLE 2.
Biodistribution and Tumor-to-Nontarget Ratios of [18F]FASu and [18F]FSPG in A549 Xenograft–Bearing Rag2M Mice
Organ [18F]FASu [18F]FSPG Unblocked (n = 6) 100 mg/kg ASu* (n = 4) Unblocked (n = 6) 100 mg/kg ASu* (n = 4) Blood 0.78 ± 0.44 0.64 ± 0.11 0.51 ± 0.08 0.55 ± 0.16 Fat 0.04 ± 0.01 0.04 ± 0.01 0.03 ± 0.01 0.02 ± 0.00 Ovaries 2.91 ± 0.50 0.91 ± 0.21† 9.13 ± 2.77 1.14 ± 0.20† Uterus 7.96 ± 2.88 0.59 ± 0.11† 6.29 ± 2.99 0.91 ± 0.34 Small intestine 2.53 ± 0.21 0.87 ± 0.61† 2.51 ± 0.37 0.46 ± 0.13† Stomach 0.66 ± 0.12 0.61 ± 0.42 0.85 ± 0.29 0.33 ± 0.18 Pancreas 24.93 ± 2.92 3.96 ± 1.18† 17.71 ± 3.63 3.99 ± 0.70† Spleen 3.89 ± 2.01 1.04 ± 0.26 6.14 ± 0.84 1.02 ± 0.20† Adrenal glands 0.65 ± 0.15 0.51 ± 0.24 0.53 ± 0.05 0.59 ± 0.16 Kidneys 13.29 ± 1.60 22.19 ± 5.85 17.49 ± 2.11 21.07 ± 10.60 Liver 0.74 ± 0.08 0.75 ± 0.17 0.63 ± 0.13 0.60 ± 0.32 Heart 0.24 ± 0.06 0.26 ± 0.05 0.16 ± 0.03 0.17 ± 0.08 Lungs 1.92 ± 0.46 2.66 ± 0.28 1.36 ± 0.07 1.00 ± 0.37 Muscle 0.15 ± 0.02 0.16 ± 0.03 0.17 ± 0.05 0.10 ± 0.03 Bone 0.56 ± 0.08 0.33 ± 0.07† 0.14 ± 0.04 0.20 ± 0.07 Brain 0.13 ± 0.02 0.09 ± 0.01 0.64 ± 0.21 0.09 ± 0.04 Tail 1.25 ± 0.20 0.75 ± 0.29 0.21 ± 0.01 0.44 ± 0.20† A549 tumor 5.00 ± 0.83 2.04 ± 0.36† 6.27 ± 1.32 3.53 ± 0.69 Tumor/blood 7.61 ± 3.58 3.22 ± 0.58 12.36 ± 2.52 6.67 ± 1.81† Tumor/muscle 33.18 ± 4.39 13.72 ± 4.40† 37.92 ± 9.55 39.15 ± 11.34 Tumor/lungs 2.70 ± 0.65 0.78 ± 0.20† 4.59 ± 0.92 3.77 ± 1.17 Tumor/brain 39.79 ± 6.67 23.40 ± 6.53† 52.95 ± 10.29 45.58 ± 17.86 - TABLE 3.
Biodistribution and Tumor-to-Nontarget Ratios of [18F]FASu and [18F]FSPG in U-87 Xenograft–Bearing Rag2M Mice
Organ [18F]FASu [18F]FSPG Organ Unblocked (n ≥ 4) Unblocked (n ≥ 4) Blood 0.84 ± 0.50 0.59 ± 0.08 Fat 0.04 ± 0.02 0.02 ± 0.00 Ovaries 3.07 ± 1.48 5.62 ± 4.09 Uterus 5.97 ± 3.08 5.07 ± 0.73 Small intestine 1.83 ± 0.64 2.18 ± 0.40 Stomach 1.66 ± 1.13 1.08 ± 0.73 Pancreas 26.42 ± 11.59 16.81 ± 1.38 Spleen 4.47 ± 1.65 6.58 ± 1.58 Adrenal glands 0.46 ± 0.15 0.55 ± 0.05 Kidneys 17.79 ± 7.20 17.92 ± 2.49 Liver 0.95 ± 0.44 0.59 ± 0.14 Heart 0.36 ± 0.21 0.17 ± 0.01 Lungs 3.41 ± 2.20 1.39 ± 0.16 Muscle 0.26 ± 0.11 0.12 ± 0.02 Bone 0.76 ± 0.46 0.76 ± 0.17 Brain 0.16 ± 0.09 0.12 ± 0.01 Tail 1.82 ± 0.90 1.26 ± 0.24 U-87 tumor 6.05 ± 2.40 11.18 ± 4.12 Tumor/blood 7.96 ± 2.81 18.67 ± 6.30 Tumor/muscle 24.08 ± 5.20 97.86 ± 38.99 Tumor/lungs 1.96 ± 0.51 8.04 ± 2.60 Tumor/brain 41.30 ± 12.73 97.22 ± 33.15 Biodistributions and ratios are at 1 h after injection. Values (%ID/g) are presented as mean ± SD.
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