Facile synthesis of carbon-11-labeled sEH/PDE4 dual inhibitors as new potential PET agents for imaging of sEH/PDE4 enzymes in neuroinflammation |
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| Affiliation: | 1. Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, College of Chemistry and Environmental Science, Hebei University, Baoding, Hebei 071002, China;3. College of Chemical & Pharmaceutical Engineering, Key Laboratory of Molecular Chemistry for Medicine of Hebei Province, Hebei University of Science & Technology, Shijiazhuang, Hebei 050018, China;4. Shijiazhuang Vince Pharmatech Co., Ltd., Shijiazhuang, Hebei 050030, China;1. Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA;2. Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA;1. Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA;2. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA;3. Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA;1. Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt;2. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, Fayoum University, 63514, Egypt;3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt;4. Department of Medicinal Chemistry, Faculty of Pharmacy, Sinai University-Kantra Branch, Egypt |
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| Abstract: | To develop PET tracers for imaging of neuroinflammation, new carbon-11-labeled sEH/PDE4 dual inhibitors have been synthesized. The reference standard N-(4-methoxy-2-(trifluoromethyl)benzyl)benzamide (1) and its corresponding desmethylated precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)benzamide (2) were synthesized from (4-methoxy-2-(trifluoromethyl)phenyl)methanamine and benzoic acid in one and two steps with 84% and 49% overall chemical yield, respectively. The standard N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA, 4) and its precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (5) were synthesized from methyl 4-piperidinecarboxylate, propionyl chloride and (4-methoxy-2-(trifluoromethyl)phenyl)methanamine in two and three steps with 62% and 34% overall chemical yield, respectively. The target tracers N-(4-[11C]methoxy-2-(trifluoromethyl)benzyl)benzamide ([11C]1) and N-(4-[11C]methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide ([11C]MPPA, [11C]4) were prepared from their corresponding precursors 2 and 5 with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 25–35% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (AM) at EOB was 370–740 GBq/μmol with a total synthesis time of 35–40-minutes from EOB. |
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| Keywords: | Soluble epoxide hydrolase (sEH) Phosphodiesterase 4 (PDE4) Carbon-11-labeled sEH/PDE4 dual inhibitors Radiosynthesis Positron emission tomography (PET) Neuroinflammation |
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