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Neural stem cells reside in two major niches in the adult brain [i.e., the subventricular zone (SVZ) and the dentate gyrus of the hippocampus]. Insults to the brain such as cerebral ischemia result in a physiological mobilization of endogenous neural stem cells. Since recent studies showed that pharmacological stimulation can be used to expand the endogenous neural stem cell niche, hope has been raised to enhance the brain's own regenerative capacity. For the evaluation of such novel therapeutic approaches, longitudinal and intraindividual monitoring of the endogenous neural stem cell niche would be required. However, to date no conclusive imaging technique has been established. We used positron emission tomography (PET) and the radiotracer 3′-deoxy-3′-[18F]fluoro-l-thymidine ([18F]FLT) that enables imaging and measuring of proliferation to noninvasively detect endogenous neural stem cells in the normal and diseased adult rat brainin vivo. This method indeed visualized neural stem cell niches in the living rat brain, identified as increased [18F]FLT-binding in the SVZ and the hippocampus. Focal cerebral ischemia and subsequent damage of the blood–brain barrier did not interfere with the capability of [18F]FLT-PET to visualize neural stem cell mobilization. Moreover, [18F]FLT-PET allowed for anin vivoquantification of increased neural stem cell mobilization caused by pharmacological stimulation or by focal cerebral ischemia. The data suggest that noninvasive longitudinal monitoring and quantification of endogenous neural stem cell activation in the brain is feasible and that [18F]FLT-PET could be used to monitor the effects of drugs aimed at expanding the neural stem cell niche.

Introduction: 18F-Fluoro-L-thymidine (18F-FLT) has been established as a non-invasive marker for tumor proliferation by positron emission tomography (PET). It has been shown that the uptake of 18F-FLT might correlate to increased transport as well as to S-phase specific thymidine kinase 1 (TK1) activity (Jacobs et al. 2005). Aim of the study was to further characterize 18F-FLT as marker for tumor activity and proliferation in patients with newly diagnosed gliomas. Material and methods: 13 patients (age: from 35 to 71y) with newly diagnosed primary brain tumors underwent 18F-FLT- and 11C-MET-PET, as well as T1- and T2-weighted MRI with and without contrast media on consecutive days. Tracer kinetics (k1, k2, k3, ki) were determined in tumor and in contralateral grey matter. The uptake of 18F-FLT was calculated by the standardized uptake value (SUV) and the tumor-to-background (T/B) ratio. Data of kinetic modelling, SUV and T/B values derived from 18F-FLT-PET were compared to T/B values derived from 11C-MET-PET and histology. Results: In 12 patients the diagnosis of a glioma was confirmed by histology (WHO III: n=6; WHO IV: n=6. In 4/6 patients with anaplastic gliomas no significant k3 value was measured. In contrast, in all patients with glioblastomas (n=6) k3 values ranged between 0,02/min and 0,015/min. The net influx constant ki correlated significantly with the FLT uptake ratio (p=0,002, r=0,78). Moreover, a significant correlation was observed between the SUV and metabolic rate constants ki and k3 with the proliferation index as measured by Ki67 immunostaining (p=0,038, r=0,604; p=0,023, r=0,65; p=0,043, r=0,60). A positive correlation was found between 11C-MET uptake and 18F-FLT uptake indicating the relationship between the increased transport of amino acids and nucleosides into the tumor (p=0,016, r=0,65). Conclusion: FLT uptake is a measure of increased uptake as measured by Ki and increased trapping in proliferating tumor cells as measured by k3at least in patients with glioblastoma. The significant correlation between ki and k3 with the histological proliferation index ki67 demonstrates that FLT uptake might be an indirect measure of tumor proliferation. Moreover, the positive correlation between 11C-MET uptake and k3 indicates, that 18F-FLT uptake is related to cell proliferation in areas with an increased microvessel density.