Kumar J S Dileep, Zanderigo Francesca, Prabhakaran Jaya, Rubin-Falcone Harry, Parsey Ramin V, Mann J John
Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, USA.
Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, USA; Department of Psychiatry, Columbia University Medical Center, New York, USA.
Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3592-3595. doi: 10.1016/j.bmcl.2018.10.049. Epub 2018 Oct 31.
Overexpression of Cyclooxygenase-2 (COX-2) enzyme is associated with the pathogenesis of inflammation, cancers, stroke, arthritis, and neurological disorders. Because of the involvement of COX-2 in these diseases, quantification of COX-2 expression using Positron Emission Tomography (PET) may be a biological marker for early diagnosis, monitoring of disease progression, and an indicator of effective treatment. At present there is no target-specific or validated PET tracer available for in vivo quantification of COX-2. The objective of this study is to evaluate [C]TMI, a selective COX-2 inhibitor (Ki ≤ 1 nM) in nonhuman primates using PET imaging. PET imaging in baboons showed that [C]TMI penetrates the blood brain barrier (BBB) and accumulates in brain in a somewhat heterogeneous pattern. Metabolite analyses indicated that [C]TMI undergoes no significant metabolism of parent tracer in the plasma for baseline scans, however a relative faster metabolism was found for blocking scan. All the tested quantification approaches provide comparable tracer total distribution volume (V) estimates in the range of 3.2-7 (mL/cm). We observed about 25% lower V values in blocking studies with meloxicam, a nonselective COX-2 inhibitor, compared to baseline [C]TMI binding. Our findings indicate that [C]TMI may be a suitable PET tracer for the quantification of COX-2 in vivo. Further experiments are needed to confirm the potential of this tracer in COX-2 overexpressing models for brain diseases.
环氧化酶-2（COX-2）的过表达与炎症、癌症、中风、关节炎和神经疾病的发病机制相关。由于COX-2参与这些疾病，使用正电子发射断层扫描（PET）对COX-2表达进行定量可能是早期诊断、监测疾病进展以及有效治疗指标的生物学标志物。目前尚无用于体内定量COX-2的靶向特异性或经过验证的PET示踪剂。本研究的目的是使用PET成像在非人类灵长类动物中评估[C]TMI，一种选择性COX-2抑制剂（Ki≤1 nM）。狒狒的PET成像显示，[C]TMI穿透血脑屏障（BBB）并以某种异质性模式在脑中蓄积。代谢物分析表明，对于基线扫描，[C]TMI在血浆中母体示踪剂无明显代谢，但在阻断扫描中发现代谢相对较快。所有测试的定量方法在3.2-7（mL/cm）范围内提供了可比的示踪剂总分布容积（V）估计值。与基线[C]TMI结合相比，我们观察到在使用非选择性COX-2抑制剂美洛昔康的阻断研究中V值降低了约25%。我们的研究结果表明，[C]TMI可能是一种适用于体内定量COX-2的PET示踪剂。需要进一步的实验来证实该示踪剂在脑疾病COX-2过表达模型中的潜力。
