title: Discovery of a high affinity and selective pyridine analog as a potential positron emission tomography imaging agent for cannabinoid type 2 receptor.
abstract: As part of our efforts to develop CB2 PET imaging agents, we investigated 2,5,6-substituted pyridines as a novel class of potential CB2 PET ligands. A total of 21 novel compounds were designed, synthesized, and evaluated for their potency and binding properties toward human and rodent CB1 and CB2. The most promising ligand 6a was radiolabeled with carbon-11 to yield 16 ([(11)C]RSR-056). Specific binding of 16 to CB2-positive spleen tissue of rats and mice was demonstrated by in vitro autogadiography and verified in vivo in PET and biodistribution experiments. Furthermore, 16 was evaluated in a lipopolysaccharid (LPS) induced murine model of neuroinflammation. Brain radioactivity was strikingly higher in the LPS-treated mice than the control mice. Compound 16 is a promising radiotracer for imaging CB2 in rodents. It might serve as a tool for the investigation of CB2 receptor expression levels in healthy tissues and different neuroinflammatory disorders in humans.
authors.affiliation: †Center for Radiopharmaceutical Sciences ETH, PSI and USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Slavik
authors.affiliation: ‡Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Uwe
authors.initials: U
authors.lastname: Grether
authors.affiliation: †Center for Radiopharmaceutical Sciences ETH, PSI and USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Müller Herde
authors.affiliation: ‡Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Gobbi
authors.affiliation: ‡Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Fingerle
authors.affiliation: ‡Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ullmer
authors.affiliation: †Center for Radiopharmaceutical Sciences ETH, PSI and USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.affiliation: †Center for Radiopharmaceutical Sciences ETH, PSI and USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.|§Department of Nuclear Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.affiliation: †Center for Radiopharmaceutical Sciences ETH, PSI and USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.|§Department of Nuclear Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Linjing
authors.initials: L
authors.lastname: Mu
authors.affiliation: †Center for Radiopharmaceutical Sciences ETH, PSI and USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
mesh_terms: D000818:Animals; D001384:Azetidines / Q000737:chemistry / Q000493:pharmacokinetics; D016466:CHO Cells; D003287:Contrast Media / Q000737:chemistry* / Q000493:pharmacokinetics*; D003412:Cricetulus; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D006801:Humans; D008297:Male; D008815:Mice, Inbred Strains; D010848:Picolinic Acids / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000737:chemistry; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D001384:Azetidines; C588309:CNR2 protein, human; D003287:Contrast Media; D010848:Picolinic Acids; D011725:Pyridines; C000600966:RSR056 azetidine; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2