title: Synthesis and biological evaluation of both enantiomers of [(18)F]flubatine, promising radiotracers with fast kinetics for the imaging of α4β2-nicotinic acetylcholine receptors.
abstract: Both enantiomers of the epibatidine analogue flubatine display high affinity towards the α4β2 nicotinic acetylcholine receptor (nAChR) in vitro, accompanied by negligible interactions with diverse off-target proteins. Extended single dose toxicity studies in rodent indicated a NOEL (No Observed Effect Level) of 6.2μg/kg for (-)-flubatine and 1.55μg/kg for (+)-flubatine. We developed syntheses for both flubatine enantiomers and their corresponding precursors for radiolabeling. The newly synthesized trimethylammonium precursors allowed for highly efficient (18)F-radiolabelling in radiochemical yields >60% and specific activities >750GBq/μmol, thus making the radioligands practical for clinical investigation.
authors.affiliation: ABX Advanced Biochemical Compounds GmbH, Heinrich-Glaeser-Strasse 10-14, D-01454 Radeberg, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Smits
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmacy, Permoserstrasse-15, D-04318 Leipzig, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmacy, Permoserstrasse-15, D-04318 Leipzig, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Hiller
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmacy, Permoserstrasse-15, D-04318 Leipzig, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmacy, Permoserstrasse-15, D-04318 Leipzig, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wenzel
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Patt
authors.affiliation: ABX Advanced Biochemical Compounds GmbH, Heinrich-Glaeser-Strasse 10-14, D-01454 Radeberg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Cumming
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmacy, Permoserstrasse-15, D-04318 Leipzig, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany.
authors.forename: Osama
authors.initials: O
authors.lastname: Sabri
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmacy, Permoserstrasse-15, D-04318 Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.affiliation: ABX Advanced Biochemical Compounds GmbH, Heinrich-Glaeser-Strasse 10-14, D-01454 Radeberg, Germany. Electronic address: hoepping@abx.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoepping
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry; D018360:Crystallography, X-Ray; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D007700:Kinetics; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013237:Stereoisomerism; D013552:Swine
chemical_list: D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; C115362:fluoronorchloroepibatidine; C403531:nicotinic receptor alpha4beta2
keywords: 2-[(18)F]FA; 2-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine; 5-[(123)I]-5-iodo-3-(2(S)-azetidinylmethoxy)pyridine; 5-[(123)I]IA; AD; Alzheimers’s disease; Alzheimers’s disease (AD); Flubatine; Fluorine-18; HPLC; Nicotinic acetylcholine receptor (nAChR); PET; PSL/mm(2); ROI; high performance liquid chromatography; nAChR; nicotinic acetylcholine receptor; p.s.; particle size; photostimulated luminescence per area; positron emission tomography; regions of interest