Abstract
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 (t1/2 = 109.8 min) and gallium-68 (t1/2 = 67.7 min) have been presented but folates labeled with “exotic” and new PET radionuclides such as copper-64 (t1/2 = 12.7 h), terbium-152 (t1/2 = 17.5 h), scandium-44 (t1/2 = 3.97 h), cobalt-55 (t1/2 = 17.5 h) and zirconium-89 (t1/2 = 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 [18F]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.
Highlights
The Family of Folates and the Folate ReceptorFolates are hydrophilic molecules and belong to the B-group vitamins
We report on folate-based radiopharmaceuticals for targeting folate receptor (FR) using PET
Ametamey and co-workers [59] designed and synthesized a new folate derivative wherein the phenyl ring in the pteroyl moiety was replaced by a pyridine ring, which resulted in an aza-folic acid derivative named 30 -aza-20 -[18 F]fluorofolic acid ([18 F]AzaFol, 16, Figure 5). [18 F]AzaFol exhibited an in vitro binding affinity (IC50 ) value of 0.8 ± 0.2 nM to FR
Summary
Folates contain a glutamate entity and a pteroyl moiety that consists of pterin and p-aminobenzoate groups (Figure 1). They are crucial for normal cellular function as they are used for the one-carbon metabolic reaction and DNA biosynthesis, repair and methylation. The family of folates consists of several chemically different molecules including folic acid (FA) and a variety of reduced tetrahydrofolates (Figure 2). In contrast to FA, reduced folates have an additional chirality center at position 6 of the pteroate group (Figure 2) that. A selection different forms of tetrahydrofolate, folates including the synthetic, fully and oxidized. FR-α is overexpressed many epithelial cancers including ovaries, uterus, kidneys, breast, of all lung and renal carcinomas express the at high levels.
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