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.