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

详细信息    查看全文

• 作者：Akihito Ohnishi^a ; Michio Senda^a ; ^{senda@fbri.org" class="auth_mail" title="E-mail the corresponding author} ; Tomohiko Yamane^a ; ^b ; Tomoko Mikami^a ; ^c ; Hiroyuki Nishida^a ; Tomoyuki Nishio^a ; Go Akamatsu^a ; Yasuhiko Ikari^a ; Shogo Kimoto^a ; Kazuki Aita^a ; Masahiro Sasaki^a ; Hiroko Shinkawa^d ; Yasuji Yamamoto^d ; Miho Shukuri^e ; ^f ; Aya Mawatari^e ; Hisashi Doi^e ; Yasuyoshi Watanabe^e ; Hirotaka Onoe^e
• 关键词：Neuroinflammation ; [11C]Ketoprofen methyl ester ; Alzheimer's disease
• 刊名：Nuclear Medicine and Biology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：43
• 期：7
• 页码：438-444
• 全文大小：1023 K

文摘

Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease (AD). As a biomarker of neuroinflammatory processes, we designed ¹¹C-labeled ketoprofen methyl ester ([¹¹C]KTP-Me) to increase the blood–brain barrier permeability of ketoprofen (KTP), a selective cyclooxygenase-1 (COX-1) inhibitor. Animal studies indicated that [¹¹C]KTP-Me enters the brain and accumulates in activated microglia of inflammatory lesions. In a first-in-human study, we reported that [¹¹C]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 [¹¹C]KTP-Me as a diagnostic biomarker of neuroinflammatory processes in AD.

Methods

[¹¹C]KTP-Me was synthesized by rapid C-[¹¹C]methylation of [¹¹C]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

[¹¹C]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

[¹¹C]KTP-Me is a new tracer that targets COX-1. [¹¹C]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 [¹¹C]KTP-Me.