Development of Folate Receptor−Targeted PET Radiopharmaceuticals for Tumor Imaging—A Bench-to-Bedside Journey

The folate receptor-α (FR-α) is overexpressed in many epithelial cancers, including ovary, uterus, kidneys, breast, lung, colon and prostate carcinomas, but shows limited expression in normal tissues such as kidneys, salivary glands, choroid plexus and placenta. FR-α has therefore emerged as a promising target for the delivery of therapeutic and imaging agents to FR-positive tumors. A series of folate-based PET (positron emission tomography) radiopharmaceuticals have been developed for the selective targeting of FR-positive malignancies. This review provides an overview on the research progress made so far regarding the design, radiosynthesis and the utility of the folate-derived PET radioconjugates for targeting FR-positive tumors. For the most part, results from folate radioconjugates labeled with fluorine-18 (t(1/2) = 109.8 min) and gallium-68 (t(1/2) = 67.7 min) have been presented but folates labeled with “exotic” and new PET radionuclides such as copper-64 (t(1/2) = 12.7 h), terbium-152 (t(1/2) = 17.5 h), scandium-44 (t(1/2) = 3.97 h), cobalt-55 (t(1/2) = 17.5 h) and zirconium-89 (t(1/2) = 78.4 h) are also discussed. For tumor imaging, none of the reported PET radiolabeled folates reported to date has made the complete bench-to-bedside journey except [(18)F]AzaFol, which made it to patients with metastatic ovarian and lung cancers in a multicenter first-in-human trial. In the near future, however, we expect more clinical trials with folate-based PET radiopharmaceuticals given the increasing clinical interest in imaging and the treatment of FR-related malignancies.