General Method for the ¹¹C‐Labeling of 2‐Arylpropionic Acids and Their Esters: Construction of a PET Tracer Library for a Study of Biological Events Involved in COXs Expression

Abstract

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.

Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer’s Disease Model Mice

“…11 C-KTP-Me is promptly and almost completely hydrolyzed to acid form, 11 C-KTP, in rat brain within 5 min after the intravenous injection and can be used with PET to visualize time-dependent changes in COX-1 in activated microglia during neuroinflammatory processes (7,8). This finding provided evidence that COX-1 plays a critical role in microglial activation during acute neuroinflammation in vivo.…”

“…According to a previous report, 11 Clabeled ketoprofen methyl ester as a racemate ((RS)-11 C-KTP-Me) was synthesized by the reaction of 11 C-CH 3 I and (3-benzophenyl)acetic acid methyl ester in the presence of bases (7). The radioactivity of the final samples including (RS)-11 C-KTP-Me was 2.5-4.0 GBq, and the specific activity was 30-50 GBq/mmol.…”

“…4A). To identify the cellular origin of (S)-11 C-KTP-Me accumulation in APP-Tg mice, we performed triple immunostaining for COX-1 or COX-2 with microglial markers Iba-1 or CD11b and Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] . Ab plaques were age-dependently increased in size and number, and COX-1 immunopositive microglia were also found in association with areas of abundant Ab (Fig.…”

Pd0-Mediated Rapid C-[11C]Methylations and C-[18F]Fluoromethylations: Revolutionary New Methodologies for the Synthesis of Short-Lived PET Molecular Probes

“…35 Consequently, we elaborated rapid 11 C labeling using the reaction of [ 11 C]CH 3 I and an enolate intermediate generated from the corresponding ester under basic conditions, 36 followed by one pot hydrolysis to convert to 11 C incorporated acid as [ [ 11 C]loxoprofen, and their corresponding esters. Notably, we found that methyl esters were particularly useful as pro radioprobes for a study of neuroinfl ammation in the brain.…”

“…The microPET studies of rats with lipopolysaccharide (LPS) induced brain infl ammation clearly showed that the radioactivity of PET probes accumulated specifi cally in the infl amed region (Figure 7), giving the fi rst successful example of the in vivo molecular imaging of neuroinfl ammation by the noninvasive PET technology. 35 A metabolite analysis in the rat brain revealed that the methyl ester intravenously administrated was initially taken up in the brain and then underwent the hydrolysis to form a pharmacologically active form of the corresponding acids. 35 Hence, we succeeded in the general 11 C labeling of 2 arenylpropionic acids and their methyl esters as PET probes of NSAIDs to construct a potentially useful PET probe library for the in vivo imaging of infl ammation involved in COX s expression.…”