title: Radiosynthesis of (S)-[18F]T1: The first PET radioligand for molecular imaging of α3β4 nicotinic acetylcholine receptors.
abstract: Recent pharmacologic data revealed the implication of α3β4 nicotinic acetylcholine receptors (nAChRs) in nicotine and drug addiction. To image α3β4 nAChRs in vivo, we aimed to establish the synthesis of a [18F]-labelled analog of the highly affine and selective α3β4 ligand (S)-3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine ((S)-T1). (S)-[18F]T1 was synthesized from ethynyl-4-[18F]fluorobenzene ([18F]5) and (S)-azidoquinuclidine by click reaction. After a synthesis time of 130min (S)-[18F]T1 was obtained with a radiochemical yield (non-decay corrected) of 4.3±1.3%, a radiochemical purity of >99% and a molar activity of >158 GBq/μmol. The brain uptake and the brain-to-blood ratio of (S)-[18F]T1 in mice at 30min post injection were 2.02 (SUV) and 6.1, respectively. According to an ex-vivo analysis, the tracer remained intact (>99%) in brain. Only one major radiometabolite was detected in plasma and urine samples. In-vitro autoradiography on pig brain slices revealed binding of (S)-[18F]T1 to brain regions associated with the expression of α3β4 nAChRs, which could be reduced by the α3β4 nAChR selective drug AT-1001. These findings make (S)-[18F]T1 a potential tool for the non-invasive imaging of α3β4 nAChRs in the brain by PET.
authors.affiliation: Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayutthaya Road, Bangkok 10400, Thailand; Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany; National Cyclotron and PET Centre, Chulabhorn Hospital, 54 Kamphaeng Phet 6 Road, Bangkok 10210, Thailand.
authors.forename: Jiradanai
authors.initials: J
authors.lastname: Sarasamkan
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Friedrich-Alexander
authors.initials: FA
authors.lastname: Ludwig
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.affiliation: Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayutthaya Road, Bangkok 10400, Thailand.
authors.forename: Kuntarat
authors.initials: K
authors.lastname: Arunrungvichian
authors.affiliation: Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayutthaya Road, Bangkok 10400, Thailand.
authors.forename: Opa
authors.initials: O
authors.lastname: Vajragupta
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany. Electronic address: p.brust@hzdr.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D051379:Mice; D057054:Molecular Imaging; D049268:Positron-Emission Tomography / Q000379:methods*; D011812:Quinuclidines / Q000138:chemical synthesis / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000378:metabolism*; D034421:Sus scrofa; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D011812:Quinuclidines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C000615276:Fluorine-18
keywords: (18)F-Radioligand (S)-[(18)F]T1; Click reaction; Drug addiction; Positron emission tomography; Radiofluorination; α3β4 Nicotinic acetylcholine receptor