Institute of Radiopharmacy, Research Center Dresden-Rossendorf, Dresden, Germany.
Eur J Med Chem. 2010 Feb;45(2):727-37. doi: 10.1016/j.ejmech.2009.11.020. Epub 2009 Nov 24.
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.
肿瘤细胞的特征是失去生长控制，这是由于细胞周期调节途径的改变，如细胞周期蛋白依赖性激酶（Cdk）活性和/或 Cdk 表达的失调。适当标记的 Cdk4 抑制剂被认为是用于通过 PET 成像细胞增殖过程和肿瘤可视化的有前途的分子探针。本工作描述了两种（124）I 标记的 Cdk4 抑制剂的设计、合成和放射性药物评价，作为体内 Cdk4 成像的潜在放射性示踪剂。用[（124）I]NaI 处理含有标记前体的溶液，可得到放射性标记的 Cdk4 抑制剂[（124）I]CKIA 和[（124）I]CKIB，放射性化学产率高达 35%。（124）I 标记的放射性示踪剂[（124）I]CKIA 和[（124）I]CKIB 用于细胞摄取研究以及 Wistar 大鼠的生物分布研究和荷瘤小鼠的小动物 PET。用[（124）I]CKIA 进行的贴壁肿瘤细胞体外放射性示踪剂摄取研究表明，在 37°C 下 1 小时后，HT-29 和 FaDu 细胞中摄取了大量放射性示踪剂[（124）I]CKIA（750-850%ID/mg 蛋白）和[（124）I]CKIB（900-1000%ID/mg 蛋白）。[（124）I]CKIA 和[（124）I]CKIB 的生物分布显示放射性示踪剂的血液清除迅速，在肝脏中积累并代谢。将两种放射性示踪剂静脉注射到 FaDu 异种移植肿瘤模型小鼠中，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 肿瘤异种移植中两种放射性示踪剂的摄取量均较少。
