title: Synthesis of a [6-pyridinyl-18F]-labelled fluoro derivative of WAY-100635 as a candidate radioligand for brain 5-HT1A receptor imaging with PET.
abstract: In recent years, considerable effort has been spent on the design, synthesis and pharmacological characterization of radiofluorinated derivatives of the 5-HT(1A) receptor antagonist, WAY-100635, for the in vivo study of these receptors in human brain with PET. (Pyridinyl-6)-fluoro- and (pyridinyl-5)-fluoro-analogues of WAY-100635 (6-fluoro and 5-fluoro-WAY-100635, 5a/6a) were synthesized as well as the corresponding chloro-, bromo- and nitro-derivatives as precursors for labelling (5b-d and 6b-d). Comparative radiolabelling of these precursors with fluorine-18 (positron-emitting isotope, 109.8 min half-life) clearly demonstrated that only ortho-fluorination in this pyridine series, and not meta-fluorination, is of interest for the preparation of a radioligand by nucleophilic heteroaromatic substitution. 6-[(18)F]Fluoro-WAY-100635 ([(18)F]5a) can be efficiently synthesized in one step, either from the corresponding 6-bromo precursor (using conventional heating at 145 degrees C for 10 min) or from the corresponding 6-nitro precursor (using microwave activation at 100 W for 1 min). Typically, 15-25 mCi (0.55-0.92 GBq) of 6-[(18)F]fluoro-WAY-100635 ([(18)F]5a, 1-2 Ci/micromol or 37-72 GBq/micromol) were obtained in 50-70 min starting from a 100 mCi (3.7 GBq) aliquot of a batch of cyclotron-produced [(18)F]fluoride. This (18)F-labelled radioligand is now being evaluated in PET studies.
authors.affiliation: Service Hospitalier Frédéric Joliot, Département de Recherche Médicale, CEA, 4 place du Général Leclerc, F-91401 Orsay, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Karramkam
authors.forename: Françoise
authors.initials: F
authors.lastname: Hinnen
authors.forename: Myriam
authors.initials: M
authors.lastname: Berrehouma
authors.forename: Christophe
authors.initials: C
authors.lastname: Hlavacek
authors.forename: Françoise
authors.initials: F
authors.lastname: Vaufrey
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Julie A
authors.initials: JA
authors.lastname: McCarron
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
mesh_terms: D001923:Brain Chemistry; D005462:Fluorine Radioisotopes; D006358:Hot Temperature; D007553:Isotope Labeling; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008872:Microwaves; D010879:Piperazines / Q000138:chemical synthesis*; D011725:Pyridines / Q000138:chemical synthesis*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D044282:Receptor, Serotonin, 5-HT1A / Q000032:analysis*; D012702:Serotonin Antagonists / Q000138:chemical synthesis*; D014055:Tomography, Emission-Computed
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide