S-enantiomer of 11C-ketoprofen-methyl ester, a potent imaging probe for COX-1 in microglial activation

413 Objectives Cyclooxygenase (COX), the prostanoid-synthesizing enzyme, plays an important role in neuroinflammatory process of several neurodegenerative diseases. Previously, we reported that 11C labeled ketoprofen-methyl ester (KTP-Me), a derivative of COX-1 selective inhibitor, could visualize activated microglia in rat model of neuroinflammation. For further improvement of specificity, we have successfully obtained S-enantiomer of 11C-KTP-Me, which is considered to be more pharmacologically active than R-, by chiral separation. In this study, we have evaluated 11C-(S)KTP-Me in vivo and applied it to Alzheimer’s disease (AD) model mice (APP-Tg) for imaging of activated microglia. Methods The specificity of 11C-(S)KTP-Me for COXs was examined in PET studies with rats which had intrastriatal injection of lipopolysaccharide(LPS). To determine the details of changes of COXs and microglial activation during progression of Aβ plaque formation in APP-Tg mice (8-24 month old), we performed ex vivo autoradiography with 11C-(S)KTP-Me and immunohistochemical studies. Results The accumulation level of 11C-(S)KTP-Me in the LPS-induced inflammatory region of rat, correlating with the in vitro COX inhibitory activity, was almost 2-fold higher than that of 11C-(R)KTP-Me. In APP-Tg mice, the apparent increase of 11C-(S)KTP-Me uptake in brain was seen from 13 month old, at which histopathological appearance of abundant Aβ plaque and activated microglia were also observed. Especially, 11C-(S)KTP-Me was highly accumulated in the frontal cortex and hippocampus, where COX-1 expressing activated microglia tightly surrounded and enclosed Aβ plaque. Conclusions 11C-(S)KTP-Me is a potent PET probe highly specific for COX-1. The studies using APP-Tg mice indicated that 11C-(S)KTP-Me could recognize COX-1 expressing activated microglia surrounding Aβ plaque, which suggests the involvement of COX-1 in neuroinflammatory process in AD.