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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Radiosynthesis and radiopharmacological evaluation of cyclin-dependent kinase 4 (Cdk4) inhibitors.
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Radiosynthesis and radiopharmacological evaluation of cyclin-dependent kinase 4 (Cdk4) inhibitors.

机译：细胞周期蛋白依赖性激酶4（Cdk4）抑制剂的放射合成和放射药理学评估。

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摘要

Tumor cells are characterized by their loss of growth control resulting from alterations in regulating pathways of the cell cycle, such as a deregulated cyclin-dependent kinase (Cdk) activity and/or Cdk expression. Appropriately radiolabeled Cdk4 inhibitors are discussed as promising molecular probes for imaging cell proliferation processes and tumor visualization by PET. This work describes the design, synthesis and radiopharmacological evaluation of two (124)I-labeled Cdk4 inhibitors as potential radiotracers for imaging of Cdk4 in vivo. Treatment of a solution containing labeling precursors with [(124)I]NaI gave radiolabeled Cdk4 inhibitors [(124)I]CKIA and [(124)I]CKIB in radiochemical yields of up to 35%. (124)I-labeled radiotracers [(124)I]CKIA and [(124)I]CKIB were used in cell uptake studies as well as biodistribution studies in Wistar rats and small-animal PET in tumor-bearing mice. In vitro radiotracer uptake studies in adherent tumor cells using [(124)I]CKIA showed substantial uptake in HT-29 and FaDu cells (750-850 %ID/mg protein [(124)I]CKIA and 900-1000 %ID/mg protein [(124)I]CKIB) after 1 h at 37 degrees C. Biodistribution of [(124)I]CKIA and [(124)I]CKIB showed rapid blood clearance of radioactivity and an accumulation as well as metabolization in the liver. Both radiotracers were administered intravenously to mouse FaDu xenograft tumor model and imaging studies were performed on a small-animal PET scanner. Both imaging techniques showed only little uptake of both radiotracers in the FaDu tumor xenografts.
机译：肿瘤细胞的特征在于其失去生长控制，这是由于细胞周期调节途径的改变，例如细胞周期蛋白依赖性激酶（Cdk）活性和/或Cdk表达失调所致。适当地使用放射性标记的Cdk4抑制剂作为有前途的分子探针进行了讨论，该探针可用于对细胞增殖过程进行成像并通过PET观察肿瘤。这项工作描述了两种（124）I标记的Cdk4抑制剂作为体内Cdk4成像的潜在放射性示踪剂的设计，合成和放射药理学评估。用[（124）I] NaI处理含有标记前体的溶液，得到放射标记的Cdk4抑制剂[（124）I] CKIA和[（124）I] CKIB，放射化学产率高达35％。 （124）I标记的放射性示踪剂[（124）I] CKIA和[（124I] CKIBIB）用于Wistar大鼠和荷瘤小鼠小动物PET的细胞摄取研究以及生物分布研究。使用[（124）I] CKIA在附着的肿瘤细胞中进行的体外放射性示踪剂吸收研究表明，HT-29和FaDu细胞可大量吸收（750-850％ID / mg蛋白[（124）I] CKIA和900-1000％ID /毫克蛋白质[（124）I] CKIB）在37摄氏度下1小时后。[（124）I] CKIA和[（124）I] CKIB的生物分布显示血液中放射性的快速清除，累积和代谢肝。将两种放射性示踪剂静脉内给予小鼠FaDu异种移植肿瘤模型，并在小动物PET扫描仪上进行成像研究。两种成像技术均显示FaDu肿瘤异种移植物中两种放射性示踪剂的摄取很少。

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