Cyclooxygenase-2 (COX-2) is involved in the inflammatory response, and its recurrent overexpression in cancers as well as in neurodegenerative disorders has made it an important target for therapy. For this reason, noninvasive imaging of COX-2 expression may represent an important diagnostic tool. In this work, a COX-2 inhibitor analogue, VA426 [1-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methyl-5-(4-(methylsulfonil)phenyl)-1H-pyrrole], was synthesized and radiolabelled with the 11C radioisotope. The ex vivo biodistribution profile of 11C-VA426 was evaluated in the brain and periphery of healthy rats and mice and in brain and periphery of inflammation models, based on the administration of LPS. 11C-VA426 synthesis with the tBuOK base showed optimal radiochemical yield (15 ± 2%) based on triflate activity, molar activity (range 37-148 GBq/μmol), and radiochemical purity (>95%). Ex vivo biodistribution studies showed a fast uptake of radioactivity but a rapid washout, except in regions expressing COX-2 (lungs, liver, and kidney) both in rats and in mice, with maximum values at 30 and 10 minutes p.i., respectively. LPS administration did not show significant effect on radioactivity accumulation. Celecoxib competition experiments performed in rats and mice treated with LPS produced a general target unrelated reduction of radioactivity concentration in all peripheral tissues and brain areas examined. Finally, in agreement with the negative results obtained from biodistribution experiments, radiometabolites analysis revealed that 11C-VA426 is highly unstable in vivo. This study indicates that the compound 11C-VA426 is not currently suitable to be used as radiopharmaceutical for PET imaging. This family of compounds needs further implementation in order to improve in vivo stability.

中文翻译：

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Cyclooxygenase-2 选择性配体 11C-VA426 的放射合成和临床前评估。

环加氧酶-2 (COX-2) 参与炎症反应，其在癌症和神经退行性疾病中反复过度表达，使其成为重要的治疗靶点。因此，COX-2 表达的无创成像可能是一种重要的诊断工具。在这项工作中，COX-2 抑制剂类似物 VA426 [1-(4-氟苯基)-3-(2-甲氧基乙基)-2-甲基-5-(4-(甲磺酰基)苯基)-1H-吡咯]合成并用 11C 放射性同位素进行放射性标记。基于 LPS 的给药，在健康大鼠和小鼠的大脑和外周以及炎症模型的大脑和外周中评估了 11C-VA426 的离体生物分布曲线。基于三氟甲磺酸酯活性、摩尔活性（范围 37-148 GBq/μmol）和放射化学纯度（> 95%），使用 tBuOK 碱合成 11C-VA426 显示出最佳放射化学产率（15 ± 2%）。离体生物分布研究表明，除了大鼠和小鼠中表达 COX-2 的区域（肺、肝和肾）外，放射性的吸收很快，但很快被清除，最大值分别出现在注射后 30 分钟和 10 分钟。LPS 给药对放射性积累没有显示出显着影响。在用 LPS 治疗的大鼠和小鼠中进行的塞来昔布竞争实验产生了与所检查的所有外周组织和脑区域中的放射性浓度无关的总体目标降低。最后，与生物分布实验获得的负面结果一致，放射性代谢物分析表明 11C-VA426 在体内高度不稳定。这项研究表明化合物11C-VA426目前不适合用作PET成像的放射性药物。该化合物家族需要进一步实施以提高体内稳定性。