What makes FDG a clinically valuable molecular imaging agent?

When the relevant clinical question revolves around the presence and extent of cancer, fluorine-18 FDG-PET/CT often generates the most precise answers. The ability of F-18 FDG to make cancer glow like a light bulb, helping to differentiate between living and dead brain tissue affected by Alzheimer's disease, has made it the radiopharmaceutical agent of choice in more than 80% of clinical PET procedures.

"FDG is so useful and beautiful, it's almost hard to believe. It distinguishes between cells that use a lot of glucose and those that don't," said Dr. Johannes Czernin, director of the nuclear medicine clinic at the University of California, Los Angeles.

The key to FDG's diagnostic power resides with its mechanism of action on a molecular level. Normally, cells use glucose as an energy supply and a raw source of carbon to create new molecules needed by the body. Ordinary glucose molecules can be transformed into FDG by replacing one hydrogen atom with a radioactive fluorine atom, a procedure carried out in a cyclotron.

Once prepared, a small amount of FDG injected into a person's bloodstream is taken up by cells as if it were normal glucose. Just like glucose, it enters cells via the Glut4 transporter, a protein spanning the cell membrane that acts like a gatekeeper for glucose. Again like glucose, FDG is then phosphorylated (a phosphate atom is added) by enzymes called hexokinases. This process ionizes FDG, preventing it from passively diffusing out of the cell. Glycolysis, a series of biochemical reactions that process glucose into smaller products, is the next step.

At this point, however, the paths of normal glucose and its altered FDG form diverge. Normal glucose, now broken down into other products, continues to be metabolized. But FDG never makes it past glycolysis. Its fluorine atom prevents it from becoming further metabolized and incorporated into cellular products. FDG just remains in the cell.

Scanning with PET detects the fluorine atom's radioactivity. From the scan, doctors and researchers can estimate FDG metabolism by using a formula that normalizes the intensity of the radioactive signal on the PET scan with the injected dose and the patient's body weight. This provides a standard uptake value.

These properties make FDG an ideal imaging agent to diagnose and monitor cancer. Cancer cells use 200 times the glucose of normal cells, acting more like selfish bacteria than cooperative body cells. FDG, therefore, accumulates in cancer cells.

FDG is also useful in imaging Alzheimer's disease in a test developed in part by Dr. Daniel Silverman at UCLA. Brain cells, particularly their distal ends, normally use large amounts of glucose. FDG accumulates in cells that are using glucose and therefore does not appear in dead cells. During the development of Alzheimer's disease, the distal ends of neurons leading to the brain's hippocampus die before the cell bodies, so the absence of FDG accumulation can reveal these areas before the cells die completely.