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.
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.
Takashima-Hirano
Misato
M
RIKEN Center for Molecular Imaging Science (CMIS), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
Shukuri
Miho
M
Takashima
Tadayuki
T
Goto
Miki
M
Wada
Yasuhiro
Y
Watanabe
Yasuyoshi
Y
Onoe
Hirotaka
H
Doi
Hisashi
H
Suzuki
Masaaki
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology*; D001769:Blood / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000378:metabolism; D004952:Esters; D007249:Inflammation / Q000201:enzymology; D008745:Methylation; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods; D011422:Propionates / Q000737:chemistry*; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002250:Carbon Radioisotopes; D052246:Cyclooxygenase 2 Inhibitors; D004952:Esters; D011422:Propionates; D011451:Prostaglandin-Endoperoxide Synthases