Development of radioiodinated pyrimidinopyridone derivatives as targeted imaging probes of activated p38α for single photon emission computed tomography
Development of radioiodinated pyrimidinopyridone derivatives as targeted imaging probes of activated p38α for single photon emission computed tomography
复制标题
开发放射性碘化嘧啶并吡啶酮衍生物作为用于单光子发射计算机断层扫描的激活 p38α 的靶向成像探针
DOI：
10.1007/s12149-021-01669-6
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发表时间：
2021
期刊：
影响因子：
2.6
通讯作者：
Temma T
中科院分区：
文献类型：
--
作者：
Hashimoto T;Kondo N;Hirata M;Temma T
目的p38 α是丝裂原活化蛋白激酶超家族成员，广泛表达于多种哺乳动物细胞中。激活的p38α可诱导对外界刺激的炎症反应，提示无创检测激活的p38α对炎症性疾病的诊断有价值。为此，我们设计了基于有效的p38α选择性抑制剂R1487的放射性标记化合物[123 I]2-IR和[123 I]4-IR，用于单光子发射计算机断层扫描（SPECT）。本研究利用123 I的放射化学性质，设计了[125 I] 2-IR和[125 I]4-IR，并对其作为p38α激活成像探针的有效性进行了评价。保留R1487的嘧啶并吡啶酮结构。我们通过7步反应合成了2-IR和4-IR。使用ADP-Glo™激酶测定系统测量2-IR、4-IR和p38α抑制剂的抑制效力。2-IR和4-IR的放射性碘化是通过使用相应的三丁基锡前体的有机锡-放射性碘交换反应进行的。在正常ddY小鼠和松节油诱导的炎症模型小鼠中，通过测定静脉给予[125 I]2-IR和[125 I]4-IR后感兴趣组织中的放射性来评价生物分布。结果合成了2-IR和4-IR，总收率分别为17.5%和19.2%。4-IR的p38α抑制效力高于2-IR;两种化合物的效力均显著低于R1487。[125 I]2-IR和[125 I]4-IR成功地从三丁基锡前体中获得，具有高放射化学产率（> 65%），纯度（> 97%）和摩尔活性（~ 81 GBq/µmol）。[125 I]4-IR显示炎症组织中有高放射性积聚（7.0 ± 1.2%D/g），迅速递送至全身，并迅速清除血液，导致高炎症/血液比（6.2 ± 0.4）和高炎症与肌肉比率（5.2 ± 1.3），而[125 I]2-IR在整个实验期间在炎症组织中显示低放射性积聚。结论[123 I] 4-IR是一种很有前途的检测p38α活性的显像剂。
Objectivep38α, a member of the mitogen-activated protein kinase superfamily, is ubiquitously expressed in a variety of mammalian cells. Activated p38α induces inflammatory responses to external stimuli, suggesting that non-invasive detection of activated p38α would be valuable for diagnosing inflammatory diseases. For this purpose, we designed radiolabeled compounds [123I]2-IR and [123I]4-IR based on a potent p38α selective inhibitor R1487 for use with single photon emission computed tomography (SPECT). In this study, we used125I instead of123I due to its more usable radiochemical properties, synthesized [125I]2-IR and [125I]4-IR, and evaluated their effectiveness as activated p38α imaging probes.Methods[123I]2-IR and [123I]4-IR were designed by introduction of a123I atom at the 2- or 4-ositions of the phenoxy ring, preserving the pyrimidinopyridone structure of R1487. We synthesized 2-IR and 4-IR via a 7-step process. The inhibitory potencies of 2-IR, 4-IR, and p38α inhibitors were measured using an ADP-Glo™ kinase assay system. Radioiodination of 2-IR and 4-IR was performed via an organotin-radioiodine exchange reaction using the corresponding tributyltin precursors. Biodistributions were evaluated by determining radioactivity in tissues of interest after intravenous administration of [125I]2-IR and [125I]4-IR in normal ddY mice and turpentine oil-induced inflammation model mice. In vivo inhibition study was also performed in inflammation model mice after intravenous administration of [125I]4-IR with pretreatment of p38α inhibitors.ResultsWe synthesized 2-IR and 4-IR at total yields of 17.5% and 19.2%, respectively. 4-IR had higher p38α inhibitory potency than 2-IR; both compounds were significantly less potent than R1487. [125I]2-IR and [125I]4-IR were successfully obtained from tributyltin precursors with high radiochemical yield (> 65%), purity (> 97%), and molar activity (~ 81 GBq/µmol). [125I]4-IR showed high radioactivity accumulation in the inflamed tissue (7.0 ± 1.2%D/g), rapid delivery throughout the body, and rapid blood clearance, resulting in a high inflammation-to-blood ratio (6.2 ± 0.4) and a high inflammation-to-muscle ratio (5.2 ± 1.3) at 30 min, while [125I]2-IR showed low radioactivity accumulation in inflamed tissue over the experimental period. Further, radioactivity accumulation in inflamed tissue after [125I]4-IR administration was significantly decreased by pretreatment with selective inhibitors.Conclusions[123I]4-IR would be a promising imaging agent for detection of activated p38α.