title: [18F]fluoro-deoxy-glucose folate: a novel PET radiotracer with improved in vivo properties for folate receptor targeting.
abstract: The folate receptor (FR) is upregulated in various cancer types (FR-α isoform) and in activated macrophages (FR-β isoform) which are involved in inflammatory and autoimmune diseases, but its expression in healthy tissues and organs is highly restricted to only a few sites (e.g kidneys). Therefore, the FR is a promising target for imaging and therapy of cancer and inflammation using folate-based radiopharmaceuticals. Herein, we report the synthesis and evaluation of a novel folic acid conjugate with improved properties suitable for positron emission tomography (PET). [(18)F]-fluoro-deoxy-glucose folate ([(18)F]3) was synthesized based on the click chemistry approach using 2-deoxy-2-[(18)F]fluoroglucopyranosyl azide and a folate alkyne derivative. The novel radiotracer [(18)F]3 was produced in good radiochemical yields (25% d.c.) and high specific radioactivity (90 GBq/μmol). Compared to previously published (18)F-folic acid derivatives, an increase in hydrophilicity was achieved by using a glucose entity as a prosthetic group. Biodistribution and PET imaging studies in KB tumor-bearing mice showed a high and specific uptake of the radiotracer in FR-positive tumors (10.03 ± 1.12%ID/g, 60 min p.i.) and kidneys (42.94 ± 2.04%ID/g, 60 min p.i.). FR-unspecific accumulation of radioactivity was only found in the liver (9.49 ± 1.13%ID/g, 60 min p.i.) and gallbladder (17.59 ± 7.22%ID/g, 60 min p.i.). No radiometabolites were detected in blood, urine, and liver tissue up to 30 min after injection of [(18)F]3. [(18)F]-fluoro-deoxy-glucose-folate ([(18)F]3) is thus a promising PET radioligand for imaging FR-positive tumors.
authors.affiliation: Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Cindy R
authors.initials: CR
authors.lastname: Fischer
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
authors.forename: Josefine
authors.initials: J
authors.lastname: Reber
authors.forename: Adrienne
authors.initials: A
authors.lastname: Müller
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
mesh_terms: D000480:Alkynes / Q000737:chemistry; D000818:Animals; D002471:Cell Transformation, Neoplastic; D057930:Click Chemistry; D005260:Female; D058975:Folate Receptor 1 / Q000378:metabolism*; D058976:Folate Receptor 2 / Q000378:metabolism*; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007624:KB Cells; D051379:Mice; D009005:Monosaccharides / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D011849:Radioactive Tracers; D011854:Radiochemistry; D002583:Uterine Cervical Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology
chemical_list: C574334:(18F)fluoro-deoxy-glucose folate; D000480:Alkynes; D058975:Folate Receptor 1; D058976:Folate Receptor 2; D009005:Monosaccharides; D011849:Radioactive Tracers; D005492:Folic Acid