title: Discovery of a fluorinated 4-oxo-quinoline derivative as a potential positron emission tomography radiotracer for imaging cannabinoid receptor type 2.
abstract: The cannabinoid receptor type 2 (CB2) is part of the endocannabinoid system and has gained growing attention in recent years because of its important role in neuroinflammatory/neurodegenerative diseases. Recently, we reported on a carbon-11 labeled 4-oxo-quinoline derivative, designated RS-016, as a promising radiotracer for imaging CB2 using PET. In this study, three novel fluorinated analogs of RS-016 were designed, synthesized, and pharmacologically evaluated. The results of our efforts led to the identification of N-(1-adamantyl)-1-(2-(2-fluoroethoxy)ethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide (RS-126) as the most potent candidate for evaluation as a CB2 PET ligand. [(18) F]RS-126 was obtained in ≥ 99% radiochemical purity with an average specific radioactivity of 98 GBq/μmol at the end of the radiosynthesis. [(18) F]RS-126 showed a logD7.4 value of 1.99 and is stable in vitro in rat and human plasma over 120 min, whereas 55% intact parent compound was found in vivo in rat blood plasma at 10 min post injection. In vitro autoradiographic studies with CB2-positive rat spleen tissue revealed high and blockable binding which was confirmed in in vivo displacement experiments with rats by dynamic PET imaging. Ex vivo biodistribution studies confirmed accumulation of [(18) F]RS-126 in rat spleen with a specificity of 79% under blocking conditions. The moderate elevated CB2 levels in LPS-treated mice brain did not permit the detection of CB2 by [(18) F]RS-126 using PET imaging. In summary, [(18) F]RS-126 demonstrated high specificity toward CB2 receptor in vitro and in vivo and is a promising radioligand for imaging CB2 receptor expression. Cannabinoid receptor type 2 (CB2) is an interesting target for PET imaging. Specific binding of [(18) F]RS-126 in CB2-positive spleen tissue (white arrow head) was confirmed in in vivo displacement experiments with rats. Time activity curve of [(18) F]RS-126 in the spleen after the addition of GW405833 (CB2 specific ligand, green) demonstrates faster radiotracer elimination (blue) compared to the tracer only (red).
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Slavik
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Müller Herde
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Achi
authors.initials: A
authors.lastname: Haider
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.affiliation: Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Weber
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.|Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland. simon.ametamey@pharma.ethz.ch.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland. linjing.mu@usz.ch.|Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland. linjing.mu@usz.ch.
authors.forename: Linjing
authors.initials: L
authors.lastname: Mu
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D005462:Fluorine Radioisotopes; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D059906:Neuroimaging / Q000379:methods; D049268:Positron-Emission Tomography / Q000379:methods*; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D015363:Quinolones / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects*; D013154:Spleen / Q000000981:diagnostic imaging; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D008070:Lipopolysaccharides; D011804:Quinolines; D015363:Quinolones; C000602794:RS-016; D019275:Radiopharmaceuticals; D043885:Receptor, Cannabinoid, CB2; D000218:Adamantane
keywords: CB2 ligands; biodistribution; fluorine-18 radiolabeling; in vitro autoradiography; neuroinflammation; positron emission tomography