Successful Live Imaging of COX-1 Enzyme Revealing the Pathogenic Mechanism of Neuroinflammation
- Development of PET Probe which selectively recognizes COX-1　in the brain

RIKEN (Ryoji Noyori, President) is the first in the world to successfully develop a new PET probe that targets the enzyme Cyclooxygenase (COX)-1, which is related to inflammation and degeneration of nerve tissue, and can visualize the increase in COX-1 function in a living brain (live-imaging) at the early stage of neuroinflammation. This has been achieved by research by Hirotaka Onoe, Team Leader, Miho Shukuri, research associate of the Functional Probe Research Laboratory, RIKEN Center for Molecular Imaging Science (Yasuyoshi Watanabe, Director), and Misato Takashima, research associate (currently a visiting scientist) of the Molecular Imaging Labeling Chemistry Laboratory (Hisashi Doi, Team Leader).

COX is the enzyme which produces an inflammation agent and has gained attention as a target for diagnosis and therapy for inflammatory diseases. There are two distinct isoforms, COX-1 which is constitutively expressed even under normal conditions, and COX-2 which is induced by an immune reaction or inflammatory stimulation. However, how COXs are specifically related to the incidence of neurodegenerative disease is still unknown.

At this time, the research group could label a derivative of ketoprofen, which shows a strong blocking effect to COX-1, by Carbon 11 (¹¹C), a radioactive nuclide, and then develop a new PET probe (¹¹C-ketoprofen methyl ester; ¹¹C-KTP-Me). Next, the PET probe was shown to specifically recognize COX-1 in the brain by the study of genetically-modified mice lacking COX-1 or COX-2 gene. Furthermore, increase in the accumulation of ¹¹C-KTP-Me in the corresponding inflammation region in the rats with neuroinflammation could be observed by PET imaging. When these rats were observed in detail at the cellular level, increased activation of immune competent cells called microglia, by inflammation reaction together with the expression of COX-1, could be identified.

The achievements at this time could verify that COX-1 plays an important role in the process of neuroinflammation. The PET imaging technique for COX-1, as a new bio-marker, can be used to evaluate the degree and progress of neuroinflammation, and is expected to contribute to the identification of the condition, diagnosis, and treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases.

This study was carried out by the Japan Advanced Molecular Imaging Program (J-AMP) and the Molecular Imaging Research Program, as commissioned by the Ministry of Education, Culture, Sports, Science and Technology, and its achievements were published in The Journal of Nuclear Medicine 52(7):1094-101, 2011.