title: Development and evaluation of novel PET tracers for imaging cannabinoid receptor type 2 in brain.
abstract: The cannabinoid receptor type 2 (CB2) has a very low expression level in brain tissue under basal conditions, but it is up-regulated in diverse pathological conditions. Two promising lead structures from the literature, N-((3S,5S,7S)-adamantan-1-yl)-8-methoxy-4-oxo-1-pentyl-1,4-dihydroquinoline-3-carboxamide and 8-butoxy-N-(2-fluoro-2-phenylethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxamide - designated KD2 and KP23, respectively - were evaluated as potential PET ligands for imaging CB2. Both KD2 and KP23 were synthesized and labeled with carbon-11. In vitro autoradiographic studies on rodent spleen tissues showed that [(11)C]KD2 exhibits superior properties. A pilot study using [(11)C]KD2 on human post mortem ALS spinal cord slices indicated high CB2 expression level and specific binding, a very exciting finding if considering the future diagnostic application of CB2 ligands and their utility in therapy monitoring. In vivo blocking studies in rats with [(11)C]KD2 showed also high specific uptake in spleen tissue. Although the protein-bound fraction is relatively high, KD2 or KD2 derivatives could be very useful tools for the non-invasive investigation of CB2 levels under various neuroinflammatory conditions.
authors.affiliation: ETH Zürich, Institute of Pharmaceutical Sciences Vladimir-Prelog-Weg 4 CH-8093 Zürich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Slavik
authors.affiliation: ETH Zürich, Institute of Pharmaceutical Sciences Vladimir-Prelog-Weg 4 CH-8093 Zürich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bieri
authors.affiliation: ETH Zürich, Institute of Pharmaceutical Sciences Vladimir-Prelog-Weg 4 CH-8093 Zürich, Switzerland.
authors.forename: Stjepko
authors.initials: S
authors.lastname: Cermak
authors.affiliation: ETH Zürich, Institute of Pharmaceutical Sciences Vladimir-Prelog-Weg 4 CH-8093 Zürich, Switzerland.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Müller
authors.affiliation: ETH Zürich, Institute of Pharmaceutical Sciences Vladimir-Prelog-Weg 4 CH-8093 Zürich, Switzerland.
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.affiliation: Muskelzentrum/ALS clinic Kantonsspital St. Gallen CH-9007 St. Gallen, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Weber
authors.affiliation: ETH Zürich, Institute of Pharmaceutical Sciences Vladimir-Prelog-Weg 4 CH-8093 Zürich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.affiliation: ETH Zürich, Institute of Pharmaceutical Sciences Vladimir-Prelog-Weg 4 CH-8093 Zürich, Switzerland. simon.ametamey@pharma.ethz.ch.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
authors.affiliation: Department of Nuclear Medicine University Hospital Zürich CH-8091 Zürich;, Email: linjing.mu@usz.ch.
authors.forename: Linjing
authors.initials: L
authors.lastname: Mu
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001344:Autopsy; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D003287:Contrast Media / Q000138:chemical synthesis*; D004285:Dogs; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D015363:Quinolones / Q000138:chemical synthesis*; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000032:analysis* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013194:Staining and Labeling
chemical_list: D002250:Carbon Radioisotopes; D003287:Contrast Media; C561593:N-(adamantan-1-yl)-8-methoxy-4-oxo-1-pentyl-1,4-dihydroquinoline-3-carboxamide; D015363:Quinolones; D043885:Receptor, Cannabinoid, CB2; D000218:Adamantane