RIKEN Center for Molecular Imaging Science, Hyogo, Japan.
J Nucl Med. 2011 Jul;52(7):1094-101. doi: 10.2967/jnumed.110.084046. Epub 2011 Jun 16.
Cyclooxygenase (COX)-1 and -2 are prostanoid-synthesizing enzymes that play important roles in the regulation of neuroinflammation and in the development of neurodegenerative disorders. However, the specific functions of these isoforms are still unclear. We recently developed (11)C-labeled ketoprofen methyl ester as a PET probe that targets the COXs for imaging neuroinflammation, though its responsible isoform is yet to be determined. In the present study, we performed ex vivo and in vivo imaging studies with (11)C-ketoprofen methyl ester and determined the contributions of the COX isoforms during the neuroinflammatory process.
To identify the COX isoform responsible for (11)C-ketoprofen methyl ester in the brain, we examined the ex vivo autoradiography of (11)C-ketoprofen methyl ester using COX-deficient mice. Time-dependent changes in accumulation of (11)C-ketoprofen methyl ester during the neuroinflammatory process were evaluated by PET in rats with hemispheric neuroinflammation induced by intrastriatal injection of lipopolysaccharide or quinolinic acid. In both rat models, cell-type specificity of COX isoform expression during neuroinflammation was identified immunohistochemically.
Ex vivo autoradiographic analysis of COX-deficient mice revealed a significant reduction of (11)C-ketoprofen methyl ester accumulation only in COX-1-deficient mice, not COX-2-deficient mice. PET of rats after intrastriatal injection of lipopolysaccharide showed a significant increase in accumulation of (11)C-ketoprofen methyl ester in the inflamed area. This increase was evident at the early phase of 6 h, peaked at day 1, and then returned to basal levels by day 7. In addition, immunohistochemical analysis revealed that the population of activated microglia and macrophages was elevated at the early phase with COX-1 expression but not COX-2. A significant increase in (11)C-ketoprofen methyl ester accumulation was also observed at day 1 after intrastriatal injection of quinolinic acid, with increased COX-1-expressing activated microglia and macrophages.
We have identified (11)C-ketoprofen methyl ester as a COX-1-selective PET probe, and using this, we have also demonstrated a time-dependent expression of COX-1 in activated microglia and macrophages during the neuroinflammatory process in the living brain. Thus, COX-1 may play a crucial role in the pathology of neuroinflammation and might be a critical target for the diagnosis and therapy of neurodegenerative disorders.
环氧化酶（COX）-1 和 -2 是前列腺素合成酶，在神经炎症的调节和神经退行性疾病的发展中发挥重要作用。然而，这些同工酶的具体功能仍不清楚。我们最近开发了（11）C 标记的酮洛芬甲酯作为一种 PET 探针，用于针对 COX 成像神经炎症，尽管其负责的同工酶尚未确定。在本研究中，我们使用（11）C-酮洛芬甲酯进行了体外和体内成像研究，并确定了 COX 同工酶在神经炎症过程中的贡献。
为了确定（11）C-酮洛芬甲酯在大脑中的 COX 同工酶，我们使用 COX 缺陷小鼠检查了（11）C-酮洛芬甲酯的体外放射自显影。通过 PET 评估了脂多糖或喹啉酸诱导的半脑神经炎症大鼠中（11）C-酮洛芬甲酯在神经炎症过程中随时间的积累变化。在这两种大鼠模型中，通过免疫组织化学鉴定了神经炎症期间 COX 同工酶表达的细胞类型特异性。
COX 缺陷小鼠的体外放射自显影分析显示，（11）C-酮洛芬甲酯的积累仅在 COX-1 缺陷小鼠中显著减少，而在 COX-2 缺陷小鼠中没有减少。脂多糖诱导的纹状体注射后大鼠的 PET 显示，炎症区域（11）C-酮洛芬甲酯的积累显著增加。这种增加在 6 小时的早期阶段明显，在第 1 天达到峰值，然后在第 7 天恢复到基础水平。此外，免疫组织化学分析显示，在 COX-1 表达但不是 COX-2 表达的早期阶段，活化的小胶质细胞和巨噬细胞数量增加。纹状体注射喹啉酸后第 1 天也观察到（11）C-酮洛芬甲酯积累的显著增加，伴有 COX-1 表达增加的活化小胶质细胞和巨噬细胞。
我们已经确定（11）C-酮洛芬甲酯是一种 COX-1 选择性 PET 探针，并使用该探针证明了在活脑的神经炎症过程中，COX-1 在活化的小胶质细胞和巨噬细胞中的时间依赖性表达。因此，COX-1 可能在神经炎症的病理中发挥关键作用，可能是神经退行性疾病诊断和治疗的关键靶点。
