title: Radiosynthesis of a ¹⁸F-labeled 2,3-diarylsubstituted indole via McMurry coupling for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo.
abstract: The radiosynthesis of 3-(4-[(18)F]fluorophenyl)-2-(4-methylsulfonylphenyl)-1H-indole [(18)F]-3 as potential PET radiotracer for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo is described. [(18)F]-3 was prepared by McMurry cyclization of a (18)F-labeled intermediate with low valent titanium and zinc via a two-step procedure in a remote controlled synthesizer unit including HPLC purification and solid phase extraction. In this way [(18)F]-3 was synthesized in 80 min synthesis time in 10% total decay corrected yield from [(18)F]fluoride in radiochemical purity >98% and a specific activity of 74-91 GBq/μmol (EOS). [(18)F]-3 was evaluated in vitro using pro-inflammatory stimulated THP-1 and COX-2 expressing tumor cell lines (FaDu, A2058, HT-29), where the radiotracer uptake was shown to be consistent with up regulated COX-2 expression. The stability of [(18)F]-3 was determined by incubation in rat whole blood and plasma in vitro and by metabolite analysis of arterial blood samples in vivo, showing with 75% of original compound after 60 min an acceptable high metabolic stability. However, no substantial tumor accumulation of [(18)F]-3 could be observed by dynamic small animal PET studies on HT-29 tumor-bearing mice in vivo. This may be due to the only moderate COX-1/COX-2 selectivity of 3 as demonstrated by both cellular and enzymatic cyclooxygenase inhibition assay in vitro. Nevertheless, the new approach first using McMurry cyclization in (18)F-chemistry gives access to (18)F-labeled diarylsubstituted heterocycles that hold promise as radiolabeled COX-2 inhibitors.
authors.affiliation: Institute of Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany. t.kniess@hzdr.de
authors.forename: Torsten
authors.initials: T
authors.lastname: Kniess
authors.forename: Markus
authors.initials: M
authors.lastname: Laube
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Fabian
authors.initials: F
authors.lastname: Sehn
authors.forename: Franziska
authors.initials: F
authors.lastname: Graf
authors.forename: Joerg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003500:Cyclization; D051546:Cyclooxygenase 2 / Q000032:analysis* / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005462:Fluorine Radioisotopes; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D013450:Sulfones / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: C575339:3-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-1H-indole; D052246:Cyclooxygenase 2 Inhibitors; D005462:Fluorine Radioisotopes; D007211:Indoles; D013450:Sulfones; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human