In the present study, we demonstrate three important findings in the comparison of imaging between 11C-4DST and 18F-FLT for clinical application. Firstly, both tracers had low-background activity in the normal brain and were able to visualize the tumor well except one non-enhancing primary diffuse astrocytoma in which both tracers failed to visualize the tumor. Both tracers had similar uptake values in the tumor, but the 18F-FLT uptake in the normal brain was relatively lower than that of 11C-4DST, resulting in better tumor visualization with 18F-FLT. Secondly, a significant correlation was observed between the Ki-67 labeling index and the uptake values of 11C-4DST and 18F-FLT in the tumor. We hypothesized that 11C-4DST is superior to 18F-FLT in evaluating cell proliferation as 11C-4DST uptake represents the whole DNA synthesis process. However, the correlation coefficients of 11C-4DST uptake values to the Ki-67 labeling index were slightly lower than those of 18F-FLT. Finally, a strong correlation was observed between the individual 11C-4DST and 18 F-FLT uptake values in the tumor.
For oncological use, measurement of the cell proliferation and DNA synthesis is an attractive target for imaging. A fluorinated thymidine analogue, 18F-FLT, has emerged as a PET tracer for evaluating tumor-proliferating activity in various brain tumors [1-4]. However, 18F-FLT has several limitations in clinical use that have been reported in previous studies [4,7-9]. Most critically, little 18F-FLT is actually incorporated into DNA synthesis, and 18F-FLT uptake in the tumor does not reflect the whole of DNA synthesis [7,8,10]. With the drawbacks of 18F-FLT, efforts were made to produce a more attractive PET tracer that can be used to evaluate tumor malignancy and cell proliferation accurately. Toyohara et al. focused on the 4′-thiothymidine (4DST) because of its metabolic stability and close similar structure to native thymidine . They synthesized 14C-labeled 4DST (14C-4DST) as a model compound of 11C-labeled alternative and demonstrated the evidence that 11C-4DST matches the concept of the ideal DNA-synthesis-imaging agent . Feasibility studies of 11C-4DST in rodent tumor models showed higher uptake than that of 18F-FLT and reflect the DNA synthesis rate [12,13]. Usefulness of 11C-4DST for the imaging of human brain tumors with PET was investigated in a recent pilot study by comparing the images of 11C-4DST and [11C]methionine (11C-MET) in six patients with various brain tumors . There was little uptake of 11C-4DST in the normal brain and rapidly growing brain tumors that were well visualized in contrast-enhanced MRI and 11C-MET PET were clearly seen in 11C-4DST PET. Although 11C-MET detected all the enhanced lesions in MRI, clinically stable (non-aggressive) tumors with enhancement were not detected with 11C-4DST. In addition, the distribution pattern of 11C-4DST in the tumor was not always identical to that of 11C-MET. Here, we report the first clinical study of comparing two nucleoside PET tracers for DNA synthesis, 11C-4DST and 18F-FLT, for in vivo imaging of human brain gliomas. 11C-4DST PET images were acquired for 15 min, beginning 15 min after the administration. The start time for imaging 11C-4DST was earlier than that for 18F-FLT PET imaging (60 min). We confirmed that 11C-4DST uptake and distribution in the tumor was almost fixed 15 min after 11C-4DST administration in a preliminary dynamic acquisition study. Two non-enhanced diffuse astrocytomas could not be visualized with 11C-4DST suggesting that 11C-4DST does not readily cross the intact BBB, and 11C-4DST uptake in the tumor rather depends on the influx through the disrupted BBB similar to 18F-FLT. The distribution pattern and uptake value of 11C-4DST in the tumor are almost identical to those of 18F-FLT except one non-enhanced primary diffuse astrocytoma and one recurrent glioblastoma with oligodendroglioma component in which only 18F-FLT could detect the tumor well, whereas 11C-4DST showed no and a faint uptake in the tumors, respectively. 11C-4DST uptake in the normal brain was visually and semiquantitatively higher than 18F-FLT. A previous clinical study reported that 11C-4DST is mainly metabolized by glucuronidation in the human body and largely accumulated in the liver . Other metabolites could be nonspecifically accumulated in the normal brain. Furthermore, a recent study has demonstrated that 4DST but not FLT can be transported via the nucleoside transporters . The active transport may cause higher uptake of 11C-4DST than 18F-FLT through the intact BBB in the normal brain though the amount of 11C-4DST transport is small.
In the present study, we examined 20 patients with various grades of gliomas and a mixture of primary and recurrent cases. There are critical limitations in the present study. Firstly, the total number of gliomas enrolled in this study was small for evaluating the usefulness of this new tracer, especially low-grade glioma. Secondary, primary, and recurrent cases should be separated when evaluating the usefulness of a BBB-dependent PET tracer, such as 11C-4DST and 18F-FLT. Recently, our research group has demonstrated that 18F-FLT PET is less useful for evaluating tumor malignancy and cell proliferation in recurrent gliomas compared with newly diagnosed gliomas . In the present study, no significant differences in the T/N ratio of 18F-FLT were noted among different glioma grades. This finding is not in accordance with the findings of our previous  and recent  studies in newly diagnosed gliomas. Moreover, there is a significant correlation between the 18F-FLT uptake and the Ki-67 labeling index, but the correlation coefficient (r = 0.50) was lower compared with the findings of our previous (r = 0.89)  and recent (r = 0.81)  studies in newly diagnosed gliomas. These discrepancies might be due to the small number of patients and mixture of primary and recurrent cases. Radiotherapy used as an adjuvant treatment for malignant gliomas may cause loosening of the endothelial tight junctions, vascular leakage, or endothelial cell death and thus can increase vascular permeability not only in the BBB but also in the blood-tumor barrier . Besides increased cell proliferation in recurrent tumors, treatment-induced breakdown of the BBB and blood-tumor barrier might contribute to the degree of 18F-FLT in the tumor. This may also be the case in 11C-4DST.
Although the short physical half-life of 11C is a significant limitation for routine clinical use, 11C-4DST has benefits with regard to lower radiation burden and diagnosis using multiple tracers in 1 day. An alternative thymidine analogue labeled with a longer half-life isotope that can be incorporated into DNA synthesis is applied`easibly for clinical use and might provide additional and alternative information. As 11C-4DST uptake represents the whole DNA synthesis process, 11C-4DST PET might be superior for evaluating treatment response and predicting prognosis compared to other tracers in patients with brain gliomas.