Exploratory human PET study of the effectiveness of 11C-ketoprofen methyl ester, a potential biomarker of neuroinflammatory processes in Alzheimer's disease

Introduction: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease (AD). As a biomarker of neuroinflammatory processes, we designed C-11-labeled ketoprofen methyl ester ([C-11] KTP-Me) to increase the blood brain barrier permeability of ketoprofen (KTP), a selective cyclooxygenase-1 (COX-1) inhibitor. Animal studies indicated that [C-11]KTP-Me enters the brain and accumulates in activated microglia of inflammatory lesions. In a first-in-human study, we reported that [C-11]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 [C-11]KTP-Me as a diagnostic biomarker of neuroinflammatory processes in AD. Methods: [C-11]KTP-Me was synthesized by rapid C-[C-11]methylation of [C-11]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 70 min 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: [C-11]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: [C-11]KTP-Me is a new tracer that targets COX-1. [C-11]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 [C-11]KTP-Me. (C) 2016 Elsevier Inc. All rights reserved.