Folic acid (folate) is a water-soluble B vitamin (1) that is essential for methylation and DNA synthesis. The primary pathway for entry of folate into cells is through the facilitated transporter, which has a low affinity for folate (Michaelis constant (Km) = 1-5 μM). Some cells in the choroid plexus, kidney, lung, thyroid, spleen, placenta, and thymus also possess a higher affinity (dissociation constant (Kd) = 0.5 nM) receptor that allows folate uptake via receptor-mediated endocytosis. Some human epithelial tumor cells were found to overexpress folate-binding protein (2). More than 90% of human ovarian and endometrial cancers express the high-affinity receptor, which is absent in normal tissues. Breast, colorectal, renal, and lung carcinomas also overexpress the folate receptor but at lower frequencies (20-50%). Activated macrophages, but not resting macrophages, have been also found to have folate receptor (3).
Several folate-based conjugates (111In-DTPA-folate, 99mTc-EC-folate and [18F]FBA-folate) have been studied in tumor imaging (4-8). Deferoxamine (DF), a chelating agent, was conjugated to folic acid forming a mixture of two isomers, DF-α-folate and DF-γ-folate. Only the DF-γ-folate isomer was able to displace [3H]folic acid from its receptors with a similar IC50 to folic acid (2.5 versus 2.4 nM) (9). 68/67/66Ga-γ-DF-folate is being developed as an imaging agent for detection of folate receptors in vivo with either positron emission tomography (PET) or single photon emission computed tomography (SPECT).