title: Development of a High-Affinity PET Radioligand for Imaging Cannabinoid Subtype 2 Receptor.
abstract: Cannabinoid receptors type 2 (CB2) represent a target with increasing importance for neuroimaging due to its upregulation under various pathological conditions. Encouraged by preliminary results obtained with [(11)C](Z)-N-(3-(2-methoxyethyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide ([(11)C]A-836339, [(11)C]1) in a mouse model of acute neuroinflammation (induced by lipopolysaccharide, LPS), we designed a library of fluorinated analogues aiming for an [(18)F]-labeled radiotracer with improved CB2 binding affinity and selectivity. Compound (Z)-N-(3-(4-fluorobutyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (29) was selected as the ligand with the highest CB2 affinity (Ki = 0.39 nM) and selectivity over those of CB1 (factor of 1000). [(18)F]29 was prepared starting from the bromo precursor (53). Specific binding was shown in vitro, whereas fast metabolism was observed in vivo in CD-1 mice. Animal PET revealed a brain uptake comparable to that of [(11)C]1. In the LPS-treated mice, a 20-30% higher uptake in brain was found in comparison to that in nontreated mice (n = 3, P < 0.05).
authors: Helmholtz-Zentrum Dresden-Rossendorf e.V., Institute of Radiopharmaceutical Cancer Research , Leipzig, Germany.
authors: Rareş-Petru
authors: RP
authors: Moldovan
authors: Helmholtz-Zentrum Dresden-Rossendorf e.V., Institute of Radiopharmaceutical Cancer Research , Leipzig, Germany.
authors: Rodrigo
authors: R
authors: Teodoro
authors: Johns Hopkins School of Medicine , Department of Radiology, Baltimore, 21287 United States.
authors: Yongjun
authors: Y
authors: Gao
authors: Helmholtz-Zentrum Dresden-Rossendorf e.V., Institute of Radiopharmaceutical Cancer Research , Leipzig, Germany.
authors: Winnie
authors: W
authors: Deuther-Conrad
authors: Helmholtz-Zentrum Dresden-Rossendorf e.V., Institute of Radiopharmaceutical Cancer Research , Leipzig, Germany.
authors: Mathias
authors: M
authors: Kranz
authors: Johns Hopkins School of Medicine , Department of Radiology, Baltimore, 21287 United States.
authors: Yuchuan
authors: Y
authors: Wang
authors: Johns Hopkins School of Medicine , Department of Radiology, Baltimore, 21287 United States.
authors: Hiroto
authors: H
authors: Kuwabara
authors: Johns Hopkins School of Medicine , Department of Radiology, Baltimore, 21287 United States.
authors: Masayoshi
authors: M
authors: Nakano
authors: Johns Hopkins School of Medicine , Department of Radiology, Baltimore, 21287 United States.
authors: Heather
authors: H
authors: Valentine
authors: Helmholtz-Zentrum Dresden-Rossendorf e.V., Institute of Radiopharmaceutical Cancer Research , Leipzig, Germany.
authors: Steffen
authors: S
authors: Fischer
authors: Johns Hopkins School of Medicine , Department of Radiology, Baltimore, 21287 United States.
authors: Martin G
authors: MG
authors: Pomper
authors: Johns Hopkins School of Medicine , Department of Radiology, Baltimore, 21287 United States.
authors: Dean F
authors: DF
authors: Wong
authors: Johns Hopkins School of Medicine , Department of Radiology, Baltimore, 21287 United States.
authors: Robert F
authors: RF
authors: Dannals
authors: Helmholtz-Zentrum Dresden-Rossendorf e.V., Institute of Radiopharmaceutical Cancer Research , Leipzig, Germany.
authors: Peter
authors: P
authors: Brust
authors: Johns Hopkins School of Medicine , Department of Radiology, Baltimore, 21287 United States.
authors: Andrew G
authors: AG
authors: Horti
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D007249:Inflammation / Q000000981:diagnostic imaging / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D059906:Neuroimaging; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D013154:Spleen / Q000000981:diagnostic imaging / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D007097:Imines; D008024:Ligands; D008070:Lipopolysaccharides; C000621122:N-(3-(4-fluorobutyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethylcyclopropanecarboxamide; D019275:Radiopharmaceuticals; D043885:Receptor, Cannabinoid, CB2; D013844:Thiazoles