title: A Promising PET Tracer for Imaging of α₇ Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand.
abstract: Changes in the expression of α₇ nicotinic acetylcholine receptors (α₇ nAChRs) in the human brain are widely assumed to be associated with neurological and neurooncological processes. Investigation of these receptors in vivo depends on the availability of imaging agents such as radioactively labelled ligands applicable in positron emission tomography (PET). We report on a series of new ligands for α₇ nAChRs designed by the combination of dibenzothiophene dioxide as a novel hydrogen bond acceptor functionality with diazabicyclononane as an established cationic center. To assess the structure-activity relationship (SAR) of this new basic structure, we further modified the cationic center systematically by introduction of three different piperazine-based scaffolds. Based on in vitro binding affinity and selectivity, assessed by radioligand displacement studies at different rat and human nAChR subtypes and at the structurally related human 5-HT₃ receptor, we selected the compound 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-fluorodibenzo-[b,d]thiophene 5,5-dioxide (10a) for radiolabeling and further evaluation in vivo. Radiosynthesis of [18F]10a was optimized and transferred to an automated module. Dynamic PET imaging studies with [18F]10a in piglets and a monkey demonstrated high uptake of radioactivity in the brain, followed by washout and target-region specific accumulation under baseline conditions. Kinetic analysis of [18F]10a in pig was performed using a two-tissue compartment model with arterial-derived input function. Our initial evaluation revealed that the dibenzothiophene-based PET radioligand [18F]10a ([18F]DBT-10) has high potential to provide clinically relevant information about the expression and availability of α₇ nAChR in the brain.
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany. r.teodoro@hzdr.de.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Teodoro
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany. m.scheunemann@hzdr.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany. w.deuther-conrad@hzdr.de.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany. b.wenzel@hzdr.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wenzel
authors.affiliation: Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Biometra-Institute University of Milan, Via Luigi Vanvitelli 32, Milano 20129, Italy. f.fasoli@in.cnr.it.
authors.forename: Francesca Maria
authors.initials: FM
authors.lastname: Fasoli
authors.affiliation: Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Biometra-Institute University of Milan, Via Luigi Vanvitelli 32, Milano 20129, Italy. c.gotti@in.cnr.it.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany. m.kranz@hzdr.de.
authors.forename: Mathias
authors.initials: M
authors.lastname: Kranz
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany. cdonat@nru.dk.
authors.forename: Cornelius K
authors.initials: CK
authors.lastname: Donat
authors.affiliation: Department of Nuclear Medicine, University Hospital Leipzig, Liebigstraße 18, Leipzig 04103, Germany. marianne.patt@medizin.uni-leipzig.de.
authors.forename: Marianne
authors.initials: M
authors.lastname: Patt
authors.affiliation: PET Center, Yale University, P.O. Box 208048, 801 Howard Avenue, New Haven, CT 06520-8048, USA. ansel.hillmer@yale.edu.
authors.forename: Ansel
authors.initials: A
authors.lastname: Hillmer
authors.affiliation: PET Center, Yale University, P.O. Box 208048, 801 Howard Avenue, New Haven, CT 06520-8048, USA. ming-qiang.zheng@yale.edu.
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.affiliation: Dan PET AB, Rosenstigen 7, Malmö SE-21619, Sweden. info@danpet.eu.
authors.forename: Dan
authors.initials: D
authors.lastname: Peters
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany. j.steinbach@hzdr.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: Department of Nuclear Medicine, University Hospital Leipzig, Liebigstraße 18, Leipzig 04103, Germany. osama.sabri@medizin.uni-leipzig.de.
authors.forename: Osama
authors.initials: O
authors.lastname: Sabri
authors.affiliation: PET Center, Yale University, P.O. Box 208048, 801 Howard Avenue, New Haven, CT 06520-8048, USA. henry.huang@yale.edu.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany. p.brust@hzdr.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000737:chemistry; D001921:Brain / Q000378:metabolism; D001931:Brain Mapping; D005462:Fluorine Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics*; D000882:Haplorhini; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008024:Ligands; D010087:Oxides; D010879:Piperazines / Q000737:chemistry; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine; D013876:Thiophenes / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D001372:Aza Compounds; D005462:Fluorine Radioisotopes; D008024:Ligands; D010087:Oxides; D010879:Piperazines; D019275:Radiopharmaceuticals; D044406:Receptors, Serotonin, 5-HT3; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor; C011758:3,7-diazabicyclo(3.3.1)nonane; C016366:dibenzothiophene
keywords: fluorine-18; neuroimaging; pharmacophore; positron emission tomography; α7 nAChR