PET Imaging of ¹⁸F-(2 S,4 R)4-Fluoroglutamine Accumulation in Breast Cancer: From Xenografts to Patients

Sustaining the growth of tumor cells requires extra energy and metabolic building blocks. In addition to consuming glucose, glutamine may play the role as an alternative source of nutrient for growth and survival. We aim to characterize a glutamine analog, ¹⁸F-(2 S,4 R)4-fluoroglutamine (¹⁸F-(2 S,4 R)4-FGln), as an imaging agent for interrogating the role of glutamine from the in vitro study of tumor cells to clinical manifestation in breast cancer patients. Purity was measured by radio-high-performance liquid chromatography (radio-HPLC), and the stability after production was evaluated in phosphate buffer saline (PBS), saline, and mouse and human serum buffers. The presence of Myc expression in MCF-7 and U87 cells was conducted using qPCR. In vitro cell uptake of ¹⁸F-(2 S,4 R)4-FGln in MCF-7 and U87 cells was directly compared with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG). In vivo biodistribution and micro-PET imaging of ¹⁸F-(2 S,4 R)4-FGln in MCF-7 bearing BALB/c nude mice were performed. PET/CT imaging of ¹⁸F-(2 S,4 R)4-FGln was compared with ¹⁸F-FDG in the same group of breast cancer patients ( n = 10). We successfully synthesized ¹⁸F-(2 S,4 R)4-FGln with a high radiochemical purity (>98%), and the radiochemical purity was unchanged in PBS and saline buffers during a 2 h incubation. In vitro cell uptake studies of ¹⁸F-(2 S,4 R)4-FGln displayed a rapid and higher uptake in MCF-7 and U87 cells as compared with ¹⁸F-FDG. Biodistribution and micro-PET images showed excellent tumor accumulation of ¹⁸F-(2 S,4 R)4-FGln in the MCF-7-implanted mice tumor model. In a preliminary clinical study, ¹⁸F-(2 S,4 R)4-FGln/PET detected more lesions in breast cancer patients than ¹⁸F-FDG/PET (90% vs 80%). Additionally, in one patient with breast lobular carcinoma, there was a lesion mean standardized uptake value (SUV_mean) and maximum standardized uptake value (SUV_max) for ¹⁸F-(2 S,4 R)4-FGln higher than those obtained by ¹⁸F-FDG, as determined by PET imaging. ¹⁸F-(2 S,4 R)4-FGln may be a useful glutamine-targeting metabolic probe for noninvasive imaging of breast cancer.