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Development of a high affinity PET radioligand for imaging cannabinoid subtype 2 receptor (CB) 2
Rares-Petru Moldovan, Rodrigo Teodoro, Yongjun Gao, Winnie Deuther-Conrad, Mathias Kranz, Yuchuan Wang, Hiroto Kuwabara, Masayoshi Nakano, Heather Valentine, Steffen Fischer, Martin G Pomper, Dean F Wong, Robert F. Dannals, Peter Brust, and Andrew G. Horti J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.6b00554 • Publication Date (Web): 08 Aug 2016 Downloaded from http://pubs.acs.org on August 15, 2016
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Journal of Medicinal Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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Journal of Medicinal Chemistry
Development of a high affinity PET radioligand for imaging cannabinoid subtype 2 receptor (CB2) Rareş-Petru Moldovan1,*, Rodrigo Teodoro1, Yongjun Gao2, Winnie Deuther-Conrad1, Mathias Kranz1, Yuchuan Wang2, Hiroto Kuwabara2, Masayoshi Nakano2, Heather Valentine2, Steffen Fischer1, Martin G. Pomper2, Dean F. Wong2, Robert F. Dannals2, Peter Brust1, Andrew G. Horti2,* 1
Helmholtz-Zentrum Dresden-Rossendorf e. V., Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany 2
Johns Hopkins School of Medicine, Department of Radiology, Baltimore, USA
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 [11C](Z)-N-(3-(2-methoxyethyl)-4,5-dimethylthiazol-2(3H)ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide ([11C]A-836339, [11C]1) in a mouse model of acute neuroinflammation (induced by lipopolysaccharide, LPS), we designed a library of fluorinated analogs aiming for an [18F]-labeled radiotracer with improved CB2 binding affinity and selectivity. Compound (Z)-N-(3-(4-fluorobutyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3tetramethyl-cyclopropanecarboxamide (29) was selected as a ligand with the highest CB2 affinity (Ki = 0.39 nM) and selectivity over CB1 (factor 1000). [18F]29 was prepared starting from the
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Journal of Medicinal Chemistry
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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 [11C]1. In the LPS treated mice, a 20-30% higher uptake in brain was found in comparison to non-treated mice (n = 3, P
