If It Works, Don’t Touch It? A Cell-Based Approach to Studying 2-[¹⁸F]FDG Metabolism

• Main Authors: Eva-Maria Klebermass, Mahshid Mahmudi, Barbara Katharina Geist, Verena Pichler, Chrysoula Vraka, Theresa Balber, Anne Miller, Arvand Haschemi, Helmut Viernstein, Nataliya Rohr-Udilova, Marcus Hacker, Markus Mitterhauser
• Format: Article
• Language: English
• Published: MDPI AG 2021-09-01
• Series: Pharmaceuticals
• Subjects: 2-[¹⁸F]FDG; 2-[¹⁸F]FDG metabolism; PET-tracer metabolism; molecular imaging; cancer metabolism
• Online Access: https://www.mdpi.com/1424-8247/14/9/910

The glucose derivative 2-[¹⁸F]fluoro-2-deoxy-D-glucose (2-[¹⁸F]FDG) is still the most used radiotracer for positron emission tomography, as it visualizes glucose utilization and energy demand. In general, 2-[¹⁸F]FDG is said to be trapped intracellularly as 2-[¹⁸F]FDG-6-phosphate, which cannot be further metabolized. However, increasingly, this dogma is being questioned because of publications showing metabolism beyond 2-[¹⁸F]FDG-6-phosphate and even postulating 2-[¹⁸F]FDG imaging to depend on the enzyme hexose-6-phosphate dehydrogenase in the endoplasmic reticulum. Therefore, we aimed to study 2-[¹⁸F]FDG metabolism in the human cancer cell lines HT1080, HT29 and Huh7 applying HPLC. We then compared 2-[¹⁸F]FDG metabolism with intracellular tracer accumulation, efflux and the cells’ metabolic state and used a graphical Gaussian model to visualize metabolic patterns. The extent of 2-[¹⁸F]FDG metabolism varied considerably, dependent on the cell line, and was significantly enhanced by glucose withdrawal. However, the metabolic pattern was quite conserved. The most important radiometabolites beyond 2-[¹⁸F]FDG-6-phosphate were 2-[¹⁸F]FDMannose-6-phosphate, 2-[¹⁸F]FDG-1,6-bisphosphate and 2-[¹⁸F]FD-phosphogluconolactone. Enhanced radiometabolite formation under glucose reduction was accompanied by reduced efflux and mirrored the cells’ metabolic switch as assessed via extracellular lactate levels. We conclude that there can be considerable metabolism beyond 2-[¹⁸F]FDG-6-phosphate in cancer cell lines and a comprehensive understanding of 2-[¹⁸F]FDG metabolism might help to improve cancer research and tumor diagnosis.