Article Figures & Data
Figures
- SCHEME 1.
Radiosynthesis and identification of 18F-(2S,4R)4F-GLN and 18F-(2S,4R)4F-GLU. HPLC = high-performance liquid chromatography; TFA = trifluoroacetic acid; UV = ultraviolet.
- FIGURE 1.
Time-dependent uptake of 18F-(2S,4R)4F-GLU, 18F-(2S,4R)4F-GLN, and 3H-GLN in PBS in 9L cells. Data are expressed as percentage of uptake in 100 μg of protein (mean ± SD, n = 3) (1-way ANOVA for cell uptake studies in 9L cells: 5 min, P < 0.001; 30 min, P < 0.001; 60 min, P = 0.004; 120 min, P = 0.001). GLN = glutamine; GLU = glutamic acid.
- FIGURE 2.
(A) Uptake of 18F-(2S,4R)4F-GLN and 18F-(2S,4R)4F-GLU in 9L cells in presence of inhibitors for systems A, ASC, L, and N and in medium free of Na+ or at various pH levels. (B) Uptake of 18F-(2S,4R)4F-GLU in presence of inhibitors for Xc− (SLC7A11) and XAG− (SLC1A1). (C) Uptake of 18F-(2S,4R)4F-GLN in presence of inhibitors for ASCT2 (SLC1A5). Uptake values are normalized to uptake of tracers in PBS in absence of inhibitors. Data are normalized uptake values (mean ± SD, n = 3). GLN = glutamine; GLU = glutamic acid.
- FIGURE 3.
Protein incorporation of 18F-(2S,4R)4F-GLN and 18F-(2S,4R)4F-GLU in 9L and SF188 tumor cell lines. 3H-GLN was used as reference ligand. Only glutamine 3H-GLN and derivative 18F-(2S,4R)4F-GLN showed significant cellular incorporation; corresponding glutamic acid derivative displayed low cell trapping. Data are percentage of TCA-insoluble fraction (% incorporation) (mean ± SD, n = 3–6) (1-way ANOVA for protein incorporation: in 9L cells, P = 0.007 [30 min], P < 0.001 [120 min]; in SF188 cells, P = 0.001 [30 min], P < 0.001 [120 min]). BCH = 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid; D-Asp = d-aspartic acid; GA = l-γ-glutamyl-anilide; GLN = glutamine; GLU = glutamic acid; GPNA = l-γ-glutamyl-p-nitroanilide; L-Ser = l-serine; MeAIB = [N-methyl]-α-methylaminoisobutyric acid; SSZ = sulfasalazine.
- FIGURE 4.
In vivo biodistribution study of 18F-(2S,4R)4F-GLU in rats bearing 9L xenografts. Data are percentage initial dose per gram, mean ± SD (n = 3).
- FIGURE 5.
Summed 120-min small-animal PET images of 18F-(2S,4R)4F-GLU (A) and 18F-(2S,4R)4F-GLN (B) in rats bearing 9L tumor model. Data represent summed 2-h scan from transverse, coronal, and sagittal views (left to right). Arrows indicate location of 9L tumors.
- FIGURE 6.
(A) Time–activity curve of 18F-(2S,4R)4F-GLU in rats bearing 9L xenograft. (B) Time–activity curve of 18F-(2S,4R)4F-GLN in rats bearing 9L xenograft. Glutamine derivative displays prolonged tumor retention, whereas glutamic acid derivative shows faster washout. (C) Comparison of tumor-to-muscle ratio of 18F-(2S,4R)4F-GLU and 18F-(2S,4R)4F-GLN.
Tables
- TABLE 1
Ratios of 18F-(2S,4R)4F-GLN* Uptake to 18F-(2S,4R)4F-GLU Uptake in Different Tumor Cell Lines
Time (min) 9L SF188 PC-3 5 1.52 ± 0.26 2.90 ± 0.85 5.56 ± 1.62 30 1.85 ± 0.35 2.57 ± 0.60 5.31 ± 1.60 60 2.59 ± 1.05 1.78 ± 0.51 4.23 ± 1.26 120 2.78 ± 1.02 1.47 ± 0.38 4.22 ± 0.55 ↵* Data were first published by Lieberman et al. (24).
- TABLE 2
Biodistribution Studies of 18F-(2S,4R)4F-GLN and 18F-(2S,4R)4F-GLU in Rats Bearing 9L Tumor After Intravenous Injection
30 min 60 min Organ 18F-(2S,4R)4F-GLU 18F-(2S,4R)4F-GLN* 18F-(2S,4R)4F-GLU 18F-(2S,4R)4F-GLN* Blood 0.36 ± 0.03 0.43 ± 0.01 0.17 ± 0.02 0.32 ± 0.02 Heart 0.16 ± 0.07 0.36 ± 0.02 0.09 ± 0.04 0.35 ± 0.01 Muscle 0.12 ± 0.07 0.37 ± 0.02 0.03 ± 0.02 0.38 ± 0.03 Lung 0.37 ± 0.34 0.64 ± 0.02 0.17 ± 0.06 0.41 ± 0.04 Kidney 3.04 ± 0.02 1.02 ± 0.12 0.99 ± 0.34 0.76 ± 0.18 Pancreas 0.20 ± 0.10 2.14 ± 0.27 0.13 ± 0.09 1.36 ± 0.16 Spleen 0.53 ± 0.22 0.76 ± 0.05 0.34 ± 0.23 0.53 ± 0.04 Liver 0.55 ± 0.12 0.98 ± 0.15 0.39 ± 0.04 0.66 ± 0.13 Skin 0.28 ± 0.05 0.42 ± 0.11 0.16 ± 0.01 0.29 ± 0.04 Brain 0.05 ± 0.01 0.11 ± 0.01 0.05 ± 0.00 0.13 ± 0.00 Bone 1.57 ± 0.44 0.78 ± 0.13 2.03 ± 0.64 1.03 ± 0.38 9L tumor 0.79 ± 0.16 1.03 ± 0.14 0.35 ± 0.25 0.76 ± 0.21 Tumor/blood 2.18 ± 0.47 2.40 ± 0.33 2.11 ± 1.52 2.38 ± 0.67 Tumor/muscle 6.36 ± 3.92 2.78 ± 0.41 11.2 ± 10.9 2.00 ± 0.57 Tumor/brain 17.6 ± 5.02 9.36 ± 1.53 7.13 ± 5.09 5.85 ± 1.61 ↵* Data were first published by Lieberman et al. (24).
Data are average percentage dose per gram, mean ± SD (n = 3 to 6).
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