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General Method for the 11 C‐Labeling of 2‐Arylpropionic Acids and Their Esters: Construction of a PET Tracer Library for a Study of Biological Events Involved in COXs Expression
Author(s) -
TakashimaHirano Misato,
Shukuri Miho,
Takashima Tadayuki,
Goto Miki,
Wada Yasuhiro,
Watanabe Yasuyoshi,
Onoe Hirotaka,
Doi Hisashi,
Suzuki Masaaki
Publication year - 2010
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200903044
Subject(s) - chemistry , ketoprofen , flurbiprofen , in vivo , metabolite , methylation , ibuprofen , cyclooxygenase , hydrolysis , prostaglandin , positron emission tomography , biochemistry , enzyme , chromatography , pharmacology , nuclear medicine , medicine , microbiology and biotechnology , gene , biology
Cyclooxygenase (COX) is a critical enzyme in prostaglandin biosynthesis that modulates a wide range of biological functions, such as pain, fever, and so on. To perform in vivo COX imaging by positron emission tomography (PET), we developed a method to incorporate 11 C radionuclide into various 2‐arylpropionic acids that have a common methylated structure, particularly among nonsteroidal anti‐inflammatory drugs (NSAIDs). Thus, we developed a novel 11 C‐radiolabeling methodology based on rapid C ‐[ 11 C]methylation by the reaction of [ 11 C]CH 3 I with enolate intermediates generated from the corresponding esters under basic conditions. One‐pot hydrolysis of the above [ 11 C]methylation products also allows the synthesis of desired 11 C‐incorporated acids. We demonstrated the utility of this method in the syntheses of six PET tracers, [ 11 C]Ibuprofen, [ 11 C]Naproxen, [ 11 C]Flurbiprofen, [ 11 C]Fenoprofen, [ 11 C]Ketoprofen, and [ 11 C]Loxoprofen. Notably, we found that their methyl esters were particularly useful as proradiotracers for a study of neuroinflammation. The microPET studies of rats with lipopolysaccharide (LPS)‐induced brain inflammation clearly showed that the radioactivity of PET tracers accumulated in the inflamed region. Among these PET tracers, the specificity of [ 11 C]Ketoprofen methyl ester was demonstrated by a blocking study. Metabolite analysis in the rat brain revealed that the methyl esters were initially taken up in the brain and then underwent hydrolysis to form pharmacologically active forms of the corresponding acids. Thus, we succeeded in general 11 C‐labeling of 2‐arylpropionic acids and their methyl esters as PET tracers of NSAIDs to construct a potentially useful PET tracer library for in vivo imaging of inflammation involved in COXs expression.