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Molecules 2015, 20(10), 18387-18421;

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

Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany
Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Biometra-Institute University of Milan, Via Luigi Vanvitelli 32, Milano 20129, Italy
Department of Nuclear Medicine, University Hospital Leipzig, Liebigstraße 18, Leipzig 04103, Germany
PET Center, Yale University, P.O. Box 208048, 801 Howard Avenue, New Haven, CT 06520-8048, USA
Dan PET AB, Rosenstigen 7, Malmö SE-21619, Sweden
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Academic Editor: Svend Borup Jensen
Received: 15 July 2015 / Revised: 25 September 2015 / Accepted: 28 September 2015 / Published: 9 October 2015
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)
Full-Text   |   PDF [1677 KB, uploaded 9 October 2015]   |  


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. View Full-Text
Keywords: α7 nAChR; pharmacophore; positron emission tomography; neuroimaging; fluorine-18 α7 nAChR; pharmacophore; positron emission tomography; neuroimaging; fluorine-18

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Teodoro, R.; Scheunemann, M.; Deuther-Conrad, W.; Wenzel, B.; Fasoli, F.M.; Gotti, C.; Kranz, M.; Donat, C.K.; Patt, M.; Hillmer, A.; Zheng, M.-Q.; Peters, D.; Steinbach, J.; Sabri, O.; Huang, Y.; Brust, P. 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. Molecules 2015, 20, 18387-18421.

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