[F]-Fluoro-2-deoxy-d-glucose-folate

[F]-Fluoro-2-deoxy-d-glucose ([F]FDG)-folate, abbreviated as [F]-5, is a conjugate of [F]-fluorodeoxyglucose and folate, which was synthesized by al Jammaz et al. for use with positron emission tomography (PET) of tumors by targeting glucose metabolism and folate receptor (1). 2-Deoxy-d-glucose (2DG) was originally synthesized to inhibit glucose utilization by cancer cells and was later labeled with F for imaging purposes (2, 3). [F]FDG, like glucose, is transported into cells by glucose transporters and converted to [F]FDG-6-phosphate ([F]FDG-6-P) within cells. Because [F]FDG-6-P cannot be further metabolized, it is then trapped within cells. Tumor cells are highly proliferative and have a high rate of glucose metabolism compared to normal tissue. Consequently, tumor cells accumulate much more [F]FDG-6-P than normal cells. PET imaging with [F]FDG ([F]FDG-PET) has been widely accepted as a standard modality in the detection, staging, and therapy response monitoring of various malignant tumors. However, there are several limitations for the clinical use of [F]FDG-PET (4, 5). First, [F]FDG can accumulate in several important organs, including the brain and heart, which not only limits its use in these organs but also causes toxicity to them. Second, [F]FDG-PET is not suitable for imaging well-differentiated, low-malignant, and slow-growing tumors because these tumors often have low glucose utilization. Third, activated inflammatory cells have been found to take up considerable [F]FDG; thus, false-positivity may become an issue when inflammatory cell infiltrate is prominent in tumors or other diseases. In an effort to develop new [F]FDG-based imaging probes, al Jammaz et al. synthesized two conjugates, [F]-5 and [F]-8, by conjugating [F]FDG with folate and methotrexate (MTX), respectively, using the readily available oxime-reactive [F]FDG building block (1). Folate is vital for the rapid proliferation of tumor cells, and folate receptor is highly affinitive and overexpressed in various types of human tumors (6, 7). In contrast, healthy cells are severely restricted in possessing folate receptors. In addition, folate conjugates have well been characterized as drugs, drug carriers, and imaging agents (8, 9). MTX is a folic acid analog but possesses a relatively low affinity for folate receptor. Studies by al Jammaz et al. showed that [F]-5 was more suitable for tumor imaging than [F]-8 (1). This chapter summarizes the data obtained with [F]-5 and [F]-8.