Ohnishi Akihito, Senda Michio, Yamane Tomohiko, Sasaki Masahiro, Mikami Tomoko, Nishio Tomoyuki, Ikari Yasuhiko, Nishida Hiroyuki, Shukuri Miho, Takashima Tadayuki, Mawatari Aya, Doi Hisashi, Watanabe Yasuyoshi, Onoe Hirotaka
Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Hyogo, Japan.
Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Hyogo, Japan.
Nucl Med Biol. 2014 Aug;41(7):594-9. doi: 10.1016/j.nucmedbio.2014.04.008. Epub 2014 Apr 13.
Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease and other brain disorders, and nonsteroidal anti-inflammatory drugs (NSAIDs) are considered therapeutic candidates. As a biomarker of neuroinflammatory processes, (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) was designed to allow cerebral penetration of ketoprofen (KTP), an active form of a selective cyclooxygenase-1 inhibitor that acts as an NSAID. Rat neuroinflammation models indicate that [(11)C]KTP-Me enters the brain and is retained in inflammatory lesions, accumulating in activated microglia. [(11)C]KTP-Me is washed out from normal tissues, leading to the present first-in-human exploratory study.
[(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor, purified with high-performance liquid chromatography, and prepared as an injectable solution including PEG400, providing radiochemical purity of >99% and specific activity of >25GBq/μmol at injection. Six young healthy male humans were injected with [(11)C]KTP-Me and scanned with PET camera to determine the early-phase brain time course followed by three whole-body scans starting 8, 20, and 40 min post-injection, together with sequential blood sampling and labeled metabolite analysis.
No adverse effects were observed during PET scanning after [(11)C]KTP-Me injection. [(11)C]KTP-Me was rapidly metabolized to (11)C-labeled ketoprofen ([(11)C]KTP) within 2-3 min and was gradually cleared from blood. The radioactivity entered the brain with an average peak cortical SUV of 1.5 at 2 min. The cortical activity was gradually washed out. Whole-body images indicated that the urinary bladder was the major excretory pathway. The organ with the highest radiation dose was the urinary bladder (average dose of 41μGy/MBq, respectively). The mean effective dose was 4.7μSv/MBq, which was comparable to other (11)C-labeled radiopharmaceuticals.
[(11)C]KTP-Me demonstrated a favorable dosimetry, biodistribution, and safety profile. [(11)C]KTP-Me entered the human brain, and the radioactivity was washed out from cerebral tissue. These data warrant further exploratory studies on patients with neuroinflammation.
神经炎症过程在阿尔茨海默病和其他脑部疾病的发病机制中起重要作用，非甾体抗炎药（NSAIDs）被视为治疗候选药物。作为神经炎症过程的生物标志物，（11）C标记的酮洛芬甲酯（[(11)C]KTP-Me）旨在使酮洛芬（KTP）能够穿透大脑，酮洛芬是一种选择性环氧化酶-1抑制剂的活性形式，起NSAID的作用。大鼠神经炎症模型表明，[(11)C]KTP-Me进入大脑并保留在炎症病变中，在活化的小胶质细胞中积聚。[(11)C]KTP-Me从正常组织中清除，从而开展了本次首例人体探索性研究。
[(11)C]KTP-Me通过[(11)C]CH3I与相应的芳基乙酸前体进行快速C-[(11)C]甲基化反应合成，用高效液相色谱法纯化，并配制成含聚乙二醇400的注射溶液，注射时放射性化学纯度>99%，比活度>25GBq/μmol。6名年轻健康男性志愿者静脉注射[(11)C]KTP-Me后，用正电子发射断层显像（PET）相机进行扫描，以确定早期脑内时间进程，随后在注射后8、20和40分钟进行三次全身扫描，并进行连续血样采集和标记代谢物分析。
注射[(11)C]KTP-Me后PET扫描期间未观察到不良反应。[(11)C]KTP-Me在2-3分钟内迅速代谢为（11）C标记的酮洛芬（[(11)C]KTP），并逐渐从血液中清除。放射性在2分钟时进入大脑，平均皮质标准化摄取值（SUV）峰值为1.5。皮质活性逐渐清除。全身图像显示膀胱是主要排泄途径。辐射剂量最高的器官是膀胱（平均剂量分别为41μGy/MBq）。平均有效剂量为4.7μSv/MBq，与其他（11）C标记的放射性药物相当。
[(11)C]KTP-Me显示出良好的剂量学、生物分布和安全性。[(11)C]KTP-Me进入人脑，放射性从脑组织中清除。这些数据为对神经炎症患者进行进一步探索性研究提供了依据。
