3'-Aza-2'-[18F]fluorofolic acid

Excerpt

Folic acid 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 (K_m) = 1–5 μM). Epithelial cells in the choroid plexus, kidney, lung, thyroid, spleen, placenta, and thymus also possess a receptor on the cell membrane with higher affinity for folate (dissociation constant (K_d) = 0.5 nM), which allows folate uptake via receptor-mediated endocytosis. Some human epithelial tumor cells have been found to overexpress the folate receptor (2). More than 90% of human ovarian and endometrial cancers express the high-affinity receptor, which is absent in the corresponding 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 also been found to have the folate receptor (3).

Several folate-based conjugates (¹¹¹In-DTPA-folate, ^99mTc-EC-folate, and ^68/67/66Ga-γ-DF-folate) have been studied in tumor imaging (4-7). Bettio et al. (8) reported the synthesis of ¹⁸F-labeled folate by reaction of [¹⁸F]4-fluorobenzylamine (FBA) with the α- and γ-carboxyl groups of folic acid. [¹⁸F]α/γ-FBA-folate has been evaluated as a positron emission tomography (PET) agent for detection of folate receptors in tumors in mice. Ross et al. (9) introduced the ¹⁸F radiolabel at the 2' position of the 4-amino-benzoyl moiety in folic acid to form 2'-[¹⁸F]fluorofolic acid (2'-[¹⁸F]FFA). 2'-[¹⁸F]FFA was found to be a specific, high-affinity PET agent for imaging folate receptor-positive tumors in mice. However, the low radiochemical yield (1%–4%) from multistep radiosynthesis limited its routine clinical use. Betzel et al. (10) replaced the phenyl ring in 2'-[¹⁸F]FFA with a pyridine ring to produce 3'-Aza-2'-[¹⁸F]fluorofolic acid (3'-Aza-2'-[¹⁸F]FFA or [¹⁸F]6) for use with PET imaging of folate receptor in nude mice bearing human nasopharyngeal carcinoma KB tumors.