Michael S. Placzek, Daniel K. Wilton, Michel Weïwer, Mariah A. Manter, Sarah E. Reid, Christopher J. Meyer, Arthur J. Campbell, Besnik Bajrami, Antoine Bigot, Sarah Bricault, Agathe Fayet, Arnaud Frouin, Frederick Gergits, Mehak Gupta, Wei Jiang, Michelle Melanson, Chiara D. Romano, Misha M. Riley, Jessica M. Wang, Hsiao-Ying Wey, Florence F. Wagner, Beth Stevens and Jacob M. Hooker*,
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Therefore, developing COX-2 positron emission tomography (PET) radiotracers for human neuroimaging is of interest. This study introduces [<sup>11</sup>C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [<sup>11</sup>C]BRD1158 was developed by prioritizing potency at COX-2, isoform selectivity over COX-1, fast binding kinetics, and free fraction in the brain. Evaluated through in vivo PET neuroimaging in rodent models with human COX-2 overexpression, [<sup>11</sup>C]BRD1158 demonstrated high brain uptake, fast target-engagement, functional reversibility, and excellent specific binding, which is advantageous for human imaging applications. Lastly, post-mortem samples from Huntington’s disease (HD) patients and preclinical HD mouse models showed that COX-2 levels were elevated specifically in disease-affected brain regions, primarily from increased expression in microglia. 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引用次数: 0
摘要
环氧化酶-2(COX-2)是一种通过前列腺素途径在外周炎症和疼痛中发挥关键作用的酶。在中枢神经系统(CNS)中,COX-2 与神经退行性疾病和精神疾病有关,是一种潜在的治疗靶点和生物标志物。然而,COX-2 的临床研究结果并不一致,部分原因是对 COX-2 活性与中枢神经系统病理学关系的机理了解有限。因此,开发用于人类神经成像的 COX-2 正电子发射断层扫描(PET)放射性同位素很有意义。本研究介绍了[11C]BRD1158,它是一种强效、独特的快速结合、选择性 COX-2 PET 放射性示踪剂。[11C]BRD1158是通过优先考虑对COX-2的效力、对COX-1的同工酶选择性、快速结合动力学和大脑中的游离部分而开发出来的。通过在人类 COX-2 过度表达的啮齿动物模型中进行体内 PET 神经成像评估,[11C]BRD1158 表现出高脑摄取率、快速靶向参与、功能可逆性和出色的特异性结合,这对人类成像应用非常有利。最后,亨廷顿氏病(HD)患者和临床前 HD 小鼠模型的尸检样本显示,COX-2 水平在受疾病影响的脑区特异性升高,主要是由于小胶质细胞中的表达增加。这些研究结果表明,COX-2有望成为HD发病和进展的新型临床标记物,这也是[11C]BRD1158人体正电子发射计算机断层成像的众多潜在应用之一。[11C]BRD1158具有快速结合和功能可逆性,有望应用于人体。此外,研究还提出了 COX-2 参与亨廷顿氏病的证据,突出了 [11C]BRD1158 与神经变性的临床和研究应用的相关性。
A Fast-Binding, Functionally Reversible, COX-2 Radiotracer for CNS PET Imaging
Cyclooxygenase-2 (COX-2) is an enzyme that plays a pivotal role in peripheral inflammation and pain via the prostaglandin pathway. In the central nervous system (CNS), COX-2 is implicated in neurodegenerative and psychiatric disorders as a potential therapeutic target and biomarker. However, clinical studies with COX-2 have yielded inconsistent results, partly due to limited mechanistic understanding of how COX-2 activity relates to CNS pathology. Therefore, developing COX-2 positron emission tomography (PET) radiotracers for human neuroimaging is of interest. This study introduces [11C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [11C]BRD1158 was developed by prioritizing potency at COX-2, isoform selectivity over COX-1, fast binding kinetics, and free fraction in the brain. Evaluated through in vivo PET neuroimaging in rodent models with human COX-2 overexpression, [11C]BRD1158 demonstrated high brain uptake, fast target-engagement, functional reversibility, and excellent specific binding, which is advantageous for human imaging applications. Lastly, post-mortem samples from Huntington’s disease (HD) patients and preclinical HD mouse models showed that COX-2 levels were elevated specifically in disease-affected brain regions, primarily from increased expression in microglia. These findings indicate that COX-2 holds promise as a novel clinical marker of HD onset and progression, one of many potential applications of [11C]BRD1158 human PET.
A COX-2 specific radiotracer for positron emission tomography imaging, [11C]BRD1158, was developed and evaluated in rodent models. [11C]BRD1158 demonstrated rapid binding and functional reversibility and shows promise for human translation. Additionally, evidence for the involvement of COX-2 in Huntington’s disease is presented, highlighting the relevance of [11C]BRD1158 to clinical and research applications in neurodegeneration.
期刊介绍:
ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.