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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-[5-11C]-glutamine. The tracer was evaluated in 9L and SF188 tumor cells (glioma and astrocytoma cell lines). The biodistribution of l-[5-11C]-glutamine in rodent tumor models was investigated by dissection and PET. Results: By reacting 11C-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-[5-11C]-glutamine was obtained (radiochemical yield, 5% at the end of synthesis; radiochemical purity, >95%). Tumor cell uptake studies showed maximum uptake of l-[5-11C]-glutamine reached 17.9% and 22.5% per 100 μg 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-[5-11C]-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-[5-11C]-glutamine might be useful for probing in vivo tumor metabolism in glutaminolytic tumors.

Humanized A33 (huA33) is a promising monoclonal antibody that recognizes A33 antigen, which is present in more than 95% of colorectal cancers and in normal bowel. In this study, we took advantage of quantitative PET to evaluate 124I huA33 targeting, biodistribution, and safety in patients with colorectal cancer. We also determined the biodistribution of 124I-huA33 when a large dose of human intravenous IgG (IVIG) was administered to manipulate the Fc receptor or when 124I-huA33 was given via hepatic arterial infusion (HAI). Methods: We studied 25 patients with primary or metastatic colorectal cancer; 19 patients had surgical exploration or resection. Patients received a median of 343 MBq (44.4–396 MBq) and 10 mg of 124I-huA33. Nineteen patients received the antibody intravenously and 6 patients via HAI, and 5 patients also received IVIG. Results: Ten of 12 primary tumors were visualized in 11 patients. The median concentration in primary colon tumors was 0.016% injected dose per gram, compared with 0.004% in normal colon. The PET-based median ratio of hepatic tumor uptake to normal-liver uptake was 3.9 (range, 1.8–22.2). Quantitation using PET, compared with well counting of serum and tissue, showed little difference. Prominent uptake in bowel hindered tumor identification in some patients. Pharmacokinetics showed that patients receiving IVIG had a significantly shorter serum half-time (41.6 ± 14.0 h) than those without (65.2 ± 9.8 h). There were no differences in clearance rates among the intravenous group, IVIG group, and HAI group, nor was there any difference in serum area under the curve, maximum serum concentration, or volume of distribution. Weak titers of human–antihuman antibodies were observed in 6 of 25 patients. No acute side effects or significant toxicities were associated with huA33. Conclusion: Good localization of 124I-huA33 in colorectal cancer with no significant toxicity has been observed. PET-derived 124I concentrations agreed well with those obtained by well counting of surgically resected tissue and blood, confirming the quantitative accuracy of 124I-huA33 PET. The HAI route had no advantage over the intravenous route. No clinically significant changes in blood clearance were induced by IVIG.

The goal of this study was to determine whether there is a potential correlation between quantification of radiolabeled macromolecular uptake in tumors determined in vivo using PET/CT and in vitro using autoradiography and γ-counting of tumor tissue.Twenty-six patients with renal masses scheduled for surgical resection received (124)I-labeled antibody cG250. Tumor specimens obtained from resection were studied. Fifteen of these patients had clear cell cancer demonstrated by positive findings on PET/CT images and histopathology. Radioactivity in tumors was measured on PET/CT images and expressed as percentage injected dose per gram. These values were then normalized to measurements of known serum radioactivity from a venous blood sample obtained at the time of PET/CT. Comparable measurements were obtained in vitro using γ-well counting and digital autoradiography of tumor tissue.There was a significant correlation between tumor radioactivity estimated in vivo and in vitro (Spearman correlation coefficient comparing normalized PET measurements with well counting of 0.84, P0.000001, and with autoradiography of 0.88, P0.000001). PET/CT measurements of tumor uptake were lower than measurements obtained with either of the in vitro methods, and digital autoradiography resulted in the highest measurements.PET/CT can be reliably used to quantify radiolabeled macromolecular uptake in vivo, suggesting important implications for quantitative pharmacokinetic estimates of macromolecular biodistribution.

This issue of the Journal of Nuclear Medicine includes a report of a promising agent for the radiopharmaceutical therapy of metastatic melanoma ([1][1]). The report is provocative for several reasons: it provides a potential unmet therapeutic need in a disease with a dismal prognosis, it underscores