Akihito Ohnishi1, Michio Senda2, Tomohiko Yamane3, Tomoko Mikami4, Hiroyuki Nishida1, Tomoyuki Nishio1, Go Akamatsu1, Yasuhiko Ikari1, Shogo Kimoto1, Kazuki Aita1, Masahiro Sasaki1, Hiroko Shinkawa5, Yasuji Yamamoto5, Miho Shukuri6, Aya Mawatari7, Hisashi Doi7, Yasuyoshi Watanabe7, Hirotaka Onoe7. 1. Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan. 2. Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan. Electronic address: senda@fbri.org. 3. Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan; Department of Nuclear Medicine, Saitama Medical University International Medical Center, Hidaka, Japan. 4. Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan; Department of Radiological Technology, Okayama Rosai Hospital, Okayama, Japan. 5. Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan. 6. Division of Bio-Function Dynamics Imaging, Center for Life Science Technologies RIKEN, Kobe, Japan; Division of Pharmaceutical Chemistry, Center Showa Pharmaceutical University, Machida, Japan. 7. Division of Bio-Function Dynamics Imaging, Center for Life Science Technologies RIKEN, Kobe, Japan.
Abstract
INTRODUCTION: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease (AD). As a biomarker of neuroinflammatory processes, we designed (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) to increase the blood-brain barrier permeability of ketoprofen (KTP), a selective cyclooxygenase-1 (COX-1) inhibitor. Animal studies indicated that [(11)C]KTP-Me enters the brain and accumulates in activated microglia of inflammatory lesions. In a first-in-human study, we reported that [(11)C]KTP-Me is a safe positron emission tomography (PET) tracer and enters the brain; the radioactivity is washed out from normal cerebral tissue. Here we explored the efficacy of [(11)C]KTP-Me as a diagnostic biomarker of neuroinflammatory processes in AD. METHODS: [(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor. Nine subjects (four healthy subjects, two Pittsburgh compound-B (PiB)-positive patients with mild cognitive impairment (MCI), and three PiB-positive AD patients) underwent a dynamic brain PET scan for 70min after injection. We evaluated differences in cortical retention and washout rate in the brain between healthy subjects and MCI/AD patients. RESULTS: A brain distribution pattern reflecting blood flow in the early-phase image was seen in both healthy subjects and MCI/AD patients. Cortical activity gradually cleared in all groups. However, we observed no obvious difference in the washout rate between healthy subjects and MCI/AD patients or between MCI and AD patients. CONCLUSIONS: [(11)C]KTP-Me cannot be useful as a potential diagnostic biomarker for MCI/AD. Further improvements in binding affinity and specificity, etc., are needed to be a diagnostic biomarker of neuroinflammation in AD. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: [(11)C]KTP-Me is a new tracer that targets COX-1. [(11)C]KTP-Me is expected to be a diagnostic biomarker of neuroinflammation in AD in the future. The effectiveness was limited in a small number of AD patients. Therefore, further studies are needed to clarify the usefulness of [(11)C]KTP-Me.
INTRODUCTION: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease (AD). As a biomarker of neuroinflammatory processes, we designed (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) to increase the blood-brain barrier permeability of ketoprofen (KTP), a selective cyclooxygenase-1 (COX-1) inhibitor. Animal studies indicated that [(11)C]KTP-Me enters the brain and accumulates in activated microglia of inflammatory lesions. In a first-in-human study, we reported that [(11)C]KTP-Me is a safe positron emission tomography (PET) tracer and enters the brain; the radioactivity is washed out from normal cerebral tissue. Here we explored the efficacy of [(11)C]KTP-Me as a diagnostic biomarker of neuroinflammatory processes in AD. METHODS:[(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor. Nine subjects (four healthy subjects, two Pittsburgh compound-B (PiB)-positive patients with mild cognitive impairment (MCI), and three PiB-positive ADpatients) underwent a dynamic brain PET scan for 70min after injection. We evaluated differences in cortical retention and washout rate in the brain between healthy subjects and MCI/ADpatients. RESULTS: A brain distribution pattern reflecting blood flow in the early-phase image was seen in both healthy subjects and MCI/ADpatients. Cortical activity gradually cleared in all groups. However, we observed no obvious difference in the washout rate between healthy subjects and MCI/ADpatients or between MCI and ADpatients. CONCLUSIONS:[(11)C]KTP-Me cannot be useful as a potential diagnostic biomarker for MCI/AD. Further improvements in binding affinity and specificity, etc., are needed to be a diagnostic biomarker of neuroinflammation in AD. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: [(11)C]KTP-Me is a new tracer that targets COX-1. [(11)C]KTP-Me is expected to be a diagnostic biomarker of neuroinflammation in AD in the future. The effectiveness was limited in a small number of ADpatients. Therefore, further studies are needed to clarify the usefulness of [(11)C]KTP-Me.
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