Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides,closely related to DPA-714, as potent ligands for imaging the TSPO 18 kDa with PET |
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| Institution: | 1. CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France;2. Inserm, U1023, Université Paris Sud, Orsay, France;3. Exploratory Unit, Sanofi, Chilly-Mazarin, France;1. Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, ERL U1164, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology, Case 256, 7 Quai St Bernard, F-75005 Paris, France;2. CNRS, UMR 8256, B2A, Biological Adaptation and Ageing, F-75005 Paris, France;3. Department of Organic Chemistry, Yerevan State University, A. Manoogian Str. 1, 0025 Yerevan, Armenia;4. Sorbonne Universités, UPMC Univ Paris 06, Atelier de Bioinformatique, Case courrier 1202, 4 Place Jussieu, F 75252 Paris Cedex 05, France;1. Department of Life Sciences, National University of Kaohsiung, Kaohsiung 811, Taiwan;2. Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 804, Taiwan;3. Department of Microbiology, Kaohsiung Medical University, Kaohsiung 807, Taiwan;4. Center of Asia-Pacific Marine Researches, National Sun Yat-Sen University, Kaohsiung, Taiwan;1. Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo Nám. 2, 166 10 Prague 6, Czech Republic;2. Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20 Prague 4, Czech Republic;1. Department of Molecular Pharmacology & Biological Chemistry, Northwestern University, 303 E. Chicago Ave, Chicago, IL 60611, United States;2. The Center for Molecular Innovation and Drug Discovery, Silverman Hall, Evanston, IL 60208, United States;3. Department of Chemistry, The Center for Molecular Innovation and Drug Discovery, Silverman Hall, Evanston, IL 60208, United States;4. Department of Neurology, Northwestern University, Chicago, IL 60611, United States |
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| Abstract: | A series of four novel analogues of DPA-714, bearing a fluoroalkynyl side chain (with a length ranging from three to six carbon atoms) in replacement of the fluoroethoxy motif, have been synthetized in six steps from commercially available methyl 4-iodobenzoate. The synthetic strategy for the preparation of these N,N-diethyl-2-(2-(4-(ω-fluoroalk-1-ynyl)phenyl)-5,7-dimethylpyrazolo1,5-a]pyrimidin-3-yl)acetamides (7a–d) consisted in derivatizing a key iodinated building block featuring the pyrazolopyrimidine acetamide backbone of DPA-714, by Sonogashira couplings with various alkynyl reagents. The resulting alkynols were subsequently fluorinated, yielding the expected target derivatives. All four analogues exhibited slightly higher affinity and selectivity towards the TSPO 18 kDa (Ki vs 3H]PK11195: 0.35–0.79 nM; Ki vs 3H]flunitrazepam: >1000 nM) when compared to DPA-714 (Ki vs 3H]PK11195: 0.91 nM; Ki vs 3H]flunitrazepam: >1000 nM). Lipophilicities (HPLC, log D7.4) increased with the chain length (from 3.6 to 4.3) and were significantly higher than the one determined for DPA-714 (2.9). Preliminary in vitro metabolism evaluation using rat microsomal incubations and LC–MS analyses showed, for all four novel analogues, the absence of defluorinated metabolites. Among them, the fluoropentynyl compound, DPA-C5yne (7c), was selected, labelled in one single step with fluorine-18 from the corresponding tosylate and in vivo evaluated with PET on our in-house-developed rat model of acute local neuroinflammation. |
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| Keywords: | DPA-714 analogues Fluorinated ligands Metabolism PET imaging |
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