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¹⁸F-Fluoro-L-Thymidine and ¹¹C-Methylmethionine as Markers of Increased Transport and Proliferation in Brain Tumors

¹ Max Planck Institute for Neurological Research, Cologne, Germany
² Department of Neurology, University of Cologne, Cologne, Germany
³ Center for Molecular Medicine, University of Cologne, Cologne, Germany

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.

Key Words: brain tumor • PET • ¹⁸F-FLT • ¹¹C-MET

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