Preparation and Characterization of L-[5-11C]-Glutamine for Metabolic Imaging of Tumors

Recently, there has been a renewed interest in the study of tumor metabolism above and beyond the Warburg effect. Studies on cancer cell metabolism have provided evidence that tumor-specific activation of signaling pathways, such as the upregulation of the oncogene myc, can regulate glutamine uptake and its metabolism through glutaminolysis to provide the cancer cell with a replacement of energy source. Methods: We report a convenient procedure to prepare L-[5-C-11]-glutamine. The tracer was evaluated in 9L and SF188 tumor cells (glioma and astrocytoma cell lines). The biodistribution of L-[5-C-11]-glutamine in rodent tumor models was investigated by dissection and PET. Results: By reacting C-11-cyanide ion with protected 4-iodo-2-amino-butanoic ester, the key intermediate was obtained in good yield. After hydrolysis with trifluoroacetic and sulfonic acids, the desired optically pure L-[5-C-11]-glutamine was obtained (radiochemical yield, 5% at the end of synthesis; radiochemical purity,> 95%). Tumor cell uptake studies showed maximum uptake of L-[5-C-11]-glutamine reached 17.9% and 22.5% per 100 mu g of protein, respectively, at 60 min in 9L and SF188 tumor cells. At 30 min after incubation, more than 30% of the activity appeared to be incorporated into cellular protein. Biodistribution in normal mice showed that L-[5-C-11]-glutamine had significant pancreas uptake (7.37 percentage injected dose per gram at 15 min), most likely due to the exocrine function and high protein turnover within the pancreas. Heart uptake was rapid, and there was 3.34 percentage injected dose per gram remaining at 60 min after injection. Dynamic small-animal PET studies in rats bearing xenografted 9L tumors and in transgenic mice bearing spontaneous mammary gland tumors showed a prominent tumor uptake and retention. Conclusion: The data demonstrated that this tracer was favorably taken up in the tumor models. The results suggest that L-[5-C-11]-glutamine might be useful for probing in vivo tumor metabolism in glutaminolytic tumors.