18F[FLT]
3'-Deoxy-3'-[18F]fluorothymidine
[18F]FLT
Barthel H, Cleij MC, Collingridge DR, et al (Cancer Research United Kingdom PET Oncology Group, Dept Cancer Med): 3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 2003, Dec 1:63:8558-9. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) has been proposed as a new marker for imaging tumor proliferation by positron emission tomography (PET). The uptake of [(18)F]FLT is regulated by cytosolic S-phase-specific thymidine kinase 1 (TK1). In this article, we have investigated the use of [(18)F]FLT to monitor the response of tumors to antiproliferative treatment in vivo. C3H/Hej mice bearing the radiation-induced fibrosarcoma 1 tumor were treated with 5-fluorouracil (5-FU; 165 mg/kg i.p.). Changes in tumor volume and biodistribution of [(18)F]FLT and 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) were measured in three groups of mice (n = 8-12/group): (a) untreated controls; (b) 24 h after 5-FU; and (c) 48 h after 5-FU. In addition, dynamic [(18)F]FLT-PET imaging was performed on a small animal scanner for 60 min. The metabolism of [(18)F]FLT in tumor, plasma, liver, and urine was determined chromatographically. Proliferation was determined by staining histological sections for proliferating cell nuclear antigen (PCNA). Tumor levels of TK1 protein and cofactor (ATP) were determined by Western blotting and bioluminescence, respectively. Tumor [(18)F]FLT uptake decreased after 5-FU treatment (47.8 +/- 7.0 and 27.1 +/- 3.7% for groups b and c, respectively, compared with group a; P < 0.001). The drug-induced reduction in tumor [(18)F]FLT uptake was significantly more pronounced than that of [(18)F]FDG. The PET image data confirmed lower tumor [(18)F]FLT retention in group c compared with group a, despite a trend toward higher radiotracer delivery for group c. Other than phosphorylation in tumors, [(18)F]FLT was found to be metabolically stable in vivo. The decrease in tumor [(18)F]FLT uptake correlated with the PCNA-labeling index (r = 0.71, P = 0.031) and tumor volume changes after 5-FU treatment (r = 0.58, P = 0.001). In this model system, the decrease in [(18)F]FLT uptake could be explained by changes in catalytic activity but not translation of TK1 protein. Compared with group a, TK1 levels were lower in group b (78.2 +/- 5.2%) but higher in group c (141.3 +/- 9.1%, P < 0.001). In contrast, a stepwise decrease in ATP levels was observed from group a to b to c (P < 0.001). In conclusion, we have demonstrated the ability to measure tumor response to antiproliferative treatment with [(18)F]FLT and PET. In our model system, the radiotracer uptake was correlated with PCNA-labeling index. The decrease in [(18)F]FLT uptake after 5-FU was more pronounced than that of [(18)F]FDG. [(18)F]FLT is, therefore, a promising marker for monitoring antiproliferative drug activity in oncology that warrants additional testing.
Jacobs AH, Thomas A, Kracht LW, et al (Max Plank Inst): 18F-flouro-l-thymidine and 11C-methylmethionine as markers of increased transport and proliferation in brain tumors. J Nuclear Med 2005:46:1948-58. Because of the high glucose metabolism in normal brain tissue 18F-FDG is not the ideal tracer for the detection of gliomas. Methyl-11C-L-methionine (11C-MET) is better suited for imaging the extent of gliomas, because it is transported specifically into tumors but only insignificantly into normal brain. 3'-Deoxy-3'-18F-fluorothymidine (18F-FLT) has been introduced as a proliferation marker in a variety of neoplasias and has promising potential for the detection of brain tumors, because its uptake in normal brain is low. Additionally, the longer half-life might permit differentiation between transport and intracellular phosphorylation. Methods: PET of 18F-FLT and 11C-MET was performed on 23 patients (age range, 20–70 y) with histologically verified gliomas of different grades. On all patients, conventional MRI was performed, and 16 patients additionally underwent contrast-enhanced imaging. Images were coregistered, and the volumes of abnormality were defined for PET and MRI. Uptake ratios and standardized uptake values (SUVs) of various tumors and regions were assessed by region-of-interest analysis. Kinetic modeling was performed on 14 patients for regional time–activity curves of 18F-FLT from tumorous and normal brain tissue. Results: Sensitivity for the detection of tumors was lower for 18F-FLT than for 11C-MET (78.3% vs. 91.3%), especially for low-grade astrocytomas. Tumor volumes detected by 18F-FLT and 11C-MET were larger than tumor regions displaying gadolinium enhancement (P < 0.01). Uptake ratios of 18F-FLT were higher than uptake ratios of 11C-MET (P < 0.01). Uptake ratios of 18F-FLT were higher in glioblastomas than in astrocytomas (P < 0.01). Absolute radiotracer uptake of 18F-FLT was low and significantly lower than that of 11C-MET (SUV, 1.3 ± 0.7 vs. 3.1 ± 1.0; P < 0.01). Some tumor regions were detected only by either 18F-FLT (7 patients) or 11C-MET (13 patients). Kinetic modeling revealed that 18F-FLT uptake in tumor tissue seems to be predominantly due to elevated transport and net influx. However, a moderate correlation was found between uptake ratio and phosphorylation rate k3 (r = 0.65 and P = 0.01 for grade II–IV gliomas; r = 0.76 and P < 0.01 for grade III–IV tumors). Conclusion: 18F-FLT is a promising tracer for the detection and characterization of primary central nervous system tumors and might help to differentiate between low- and high-grade gliomas. 18F-FLT uptake is mainly due to increased transport, but irreversible incorporation by phosphorylation might also contribute. In some tumors and tumor areas, 18F-FLT uptake is not related to 11C-MET uptake. In view of the high sensitivity and specificity of 11C-MET PET for imaging of gliomas, it cannot be excluded that 18F-FLT PET was false positive in these areas. However, the discrepancies observed for the various imaging modalities (18F-FLT and 11C-MET PET as well as gadolinium-enhanced MRI) yield complementary information on the activity and the extent of gliomas and might improve early evaluation of treatment effects, especially in patients with high-grade gliomas. Further studies are needed, including coregistered histology and kinetic analysis in patients undergoing chemotherapy.
Chen W, Cloughesy T, Kamdar N, ...Mischel P, et al (UCLA): Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F FDG. 3'-Deoxy-3'-18F-fluorothymidine (18F-FLT) is a recently developed PET tracer to image tumor cell proliferation. We characterized 18F-FLT PET of brain gliomas and compared 18F-FLT with 18F-FDG PET in side-by-side studies of the same patients. Methods: Twenty-five patients with newly diagnosed or previously treated glioma underwent PET with 18F-FLT and 18F-FDG on consecutive days. Three stable patients in long-term remission were included as negative control subjects. Tracer kinetics in normal brain and tumor were measured. Uptake of 18F-FLT and 18F-FDG was quantified by the standardized uptake value (SUV) and the tumor-to-normal tissue (T/N) ratio. The accuracy of 18F-FLT and 18F-FDG PET in evaluating newly diagnosed and recurrent gliomas was compared. More than half of the patients underwent resection after the PET study and correlations between PET uptake and the Ki-67 proliferation index were examined. Patients were monitored for a mean of 15.4 mo (range, 12–20 mo). The predictive power of PET for tumor progression and survival was analyzed using Kaplan–Meier statistics. Results: 18F-FLT uptake in tumors was rapid, peaking at 5–10 min after injection and remaining stable up to 75 min. Hence, a 30-min scan beginning at 5 min after injection was sufficient for imaging. 18F-FLT visualized all high-grade (grade III or IV) tumors. Grade II tumor did not show appreciable 18F-FLT uptake and neither did the stable lesions. The absolute uptake of 18F-FLT was low (maximum-pixel SUV [SUVmax], 1.33) but image contrast was better than with 18F-FDG (T/N ratio, 3.85 vs. 1.49). 18F-FDG PET studies were negative in 5 patients with recurrent high-grade glioma who subsequently suffered tumor progression within 1–3 mo. 18F-FLT SUVmax correlated more strongly with Ki-67 index (r = 0.84; P < 0.0001) than 18F-FDG SUVmax (r = 0.51; P = 0.07). 18F-FLT uptake also had more significant predictive power with respect to tumor progression and survival (P = 0.0005 and P = 0.001, respectively). Conclusion: Thirty-minute 18F-FLT PET 5 min after injection was more sensitive than 18F-FDG to image recurrent high-grade tumors, correlated better with Ki-67 values, and was a more powerful predictor of tumor progression and survival. Thus, 18F-FLT appears to be a promising tracer as a surrogate marker of proliferation in high-grade gliomas.