title: Synthesis of a fluorine-18-labelled derivative of 6-nitroquipazine, as a radioligand for the in vivo serotonin transporter imaging with PET.
abstract: Considerable efforts have been engaged in the design, synthesis and pharmacological characterization of radioligands for imaging the serotonin transporter, based on its implication in several neuropsychiatric diseases, such as depression, anxiety and schizophrenia. In the 5-halo-6-nitroquipazine series, the fluoro derivative has been designed for positron emission tomography (PET). The corresponding 5-iodo-, 5-bromo- and 5-chloro N-Boc-protected quipazines as labelling precursors, as well as 5-fluoro-6-nitroquipazine as a reference compound have been synthesized. 5-[(18)F]Fluoro-6-nitroquipazine has been radiolabelled with fluorine-18 (positron-emitting isotope, 109.8 min half-life) by nucleophilic aromatic substitution from the corresponding N-Boc protected 5-bromo- and 5-chloro-precursors using K[(18)F]F-K(222) complex in DMSO by conventional heating (145 degrees C, 2 min) or microwave activation (50 W, 30-45 s), followed by removal of the protective group with TFA. Typically, 15-25 mCi (5.5-9.2 GBq) of 5-[(18)F]fluoro-6-nitroquipazine (1-2 Ci/micromol or 37-72 GBq/micromol) could be obtained in 70-80 min starting from a 550-650 mCi (20.3-24.0 GBq) aliquot of a cyclotron [(18)F]F(-) production batch (2.7-3.8% non decay-corrected yield based on the starting [(18)F]fluoride). Ex vivo studies (biodistribution in rat), as well as PET imaging (in monkey) demonstrated that 5-[(18)F]fluoro-6-nitroquipazine ([(18)F]-1d) readily crossed the blood brain barrier and accumulated in the regions rich in 5-HT transporter (frontal- and posterial cortex, striata). However, the low accumulation of the tracer in the thalamus (rat and monkey) as well as the comparable displacement of the tracer observed with both citalopram, a -HT re-uptake inhibitor and maprotiline, a norepinephrine re-uptake inhibitor (rat), indicate that 5-[(18)F]fluoro-6-nitroquipazine ([(18)F]-1d) does not have the suggested potential for PET imaging of the serotin transporter (SERT).
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: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.forename: Héric
authors.initials: H
authors.lastname: Valette
authors.forename: Laurent
authors.initials: L
authors.lastname: Besret
authors.forename: Yann
authors.initials: Y
authors.lastname: Bramoullé
authors.forename: Françoise
authors.initials: F
authors.lastname: Hinnen
authors.forename: Françoise
authors.initials: F
authors.lastname: Vaufrey
authors.forename: Carine
authors.initials: C
authors.lastname: Franklin
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bourg
authors.forename: Christine
authors.initials: C
authors.lastname: Coulon
authors.forename: Michèle
authors.initials: M
authors.lastname: Ottaviani
authors.forename: Marcel
authors.initials: M
authors.lastname: Delaforge
authors.forename: Christian
authors.initials: C
authors.lastname: Loc'h
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
authors.forename: Christian
authors.initials: C
authors.lastname: Crouzel
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001812:Blood-Brain Barrier; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D000882:Haplorhini; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011814:Quipazine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000592:standards; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: D002352:Carrier Proteins; D005462:Fluorine Radioisotopes; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D011814:Quipazine; C031227:6-nitroquipazine