Cytosolic phospholipase A2α (cPLA2α) may play a critical role in neuropsychiatric and neurodegenerative disorders associated with oxidative stress and neuroinflammation. An effective PET radioligand for imaging cPLA2α in living brain might prove useful for biomedical research, especially on neuroinflammation. We selected four high-affinity (IC50 2.1-12 nm) indole-5-carboxylic acid-based inhibitors of cPLA2α, namely 3-isobutyryl-1-(2-oxo-3-(4-phenoxyphenoxy)propyl)-1H-indole-5-carboxylic acid (1); 3-acetyl-1-(2-oxo-3-(4-(4-(trifluoromethyl)phenoxy)phenoxy)propyl)-1H-indole-5-carboxylic acid (2); 3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-(2-oxo-3-(4-phenoxyphenoxy)propyl)-1H-indole-5-carboxylic acid (3); and 3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-(3-(4-octylphenoxy)-2-oxopropyl)-1H-indole-5-carboxylic acid (4), for labelling in carboxyl position with carbon-11 (t1/2 =20.4 min) to provide candidate PET radioligands for imaging brain cPLA2α. Compounds [11 C]1-4 were obtained for intravenous injection in adequate overall yields (1.1-5.5 %) from cyclotron-produced [11 C]carbon dioxide and with moderate molar activities (70-141 GBq μmol-1 ) through the use of Pd0 -mediated [11 C]carbon monoxide insertion on iodo precursors. Measured logD7.4 values were within a narrow moderate range (1.9-2.4). After intravenous injection of [11 C]1-4 in mice, radioactivity uptakes in brain peaked at low values (≤0.8 SUV) and decreased by about 90 % over 15 min. Pretreatments of the mice with high doses of the corresponding non-radioactive ligands did not alter brain time-activity curves. Brain uptakes of radioactivity after administration of [11 C]1 to wild-type and P-gp/BCRP dual knock-out mice were similar (peak 0.4 vs. 0.5 SUV), indicating that [11 C]1 and others in this structural class, are not substrates for efflux transporters.

中文翻译：

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[Carboxyl-11 C] 四种高亲和力 cPLA2α 抑制剂的标记及其在小鼠中作为放射性配体的正电子发射断层扫描评估。

胞质磷脂酶 A2α (cPLA2α) 可能在与氧化应激和神经炎症相关的神经精神和神经退行性疾病中发挥关键作用。用于在活脑中成像 cPLA2α 的有效 PET 放射性配体可能对生物医学研究有用，特别是在神经炎症方面。我们选择了四种高亲和力 (IC50 2.1-12 nm) 吲哚-5-羧酸基 cPLA2α 抑制剂，即 3-isobutyryl-1-(2-oxo-3-(4-phenoxyphenoxy)propyl)-1H-indole -5-羧酸（1）；3-乙酰基-1-(2-氧代-3-(4-(4-(三氟甲基)苯氧基)苯氧基)丙基)-1H-吲哚-5-羧酸(2)；3-(3-甲基-1,2,4-恶二唑-5-基)-1-(2-氧代-3-(4-苯氧基苯氧基)丙基)-1H-吲哚-5-羧酸(3)；和3-(3-甲基-1,2,4-恶二唑-5-基)-1-(3-(4-辛基苯氧基)-2-氧代丙基)-1H-吲哚-5-羧酸(4)，用于在羧基位置用碳 11 标记（t1/2 = 20.4 分钟），为脑 cPLA2α 成像提供候选 PET 放射性配体。通过使用回旋加速器产生的 [11 C] 二氧化碳和具有中等摩尔活性 (70-141 GBq μmol-1 ) 的化合物 [11 C]1-4 获得了足够的总产率 (1.1-5.5 %) 用于静脉内注射Pd0 介导的 [11 C] 一氧化碳在碘前体上的插入。测得的 logD7.4 值在一个狭窄的中等范围内 (1.9-2.4)。小鼠静脉注射 [11 C]1-4 后，脑中的放射性摄取在低值（≤0.8 SUV）时达到峰值，并在 15 分钟内下降约 90%。用高剂量的相应非放射性配体对小鼠进行预处理不会改变大脑时间-活动曲线。