Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, PR China.
Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, PR China.
Eur J Med Chem. 2020 Feb 15;188:112032. doi: 10.1016/j.ejmech.2019.112032. Epub 2020 Jan 3.
Overexpression and amplification of cyclin-dependent kinase 4/6 (CDK4/6) occur in many cancers and may be the cause of resistance to CDK4/6 inhibitors in preclinical models. However, there are few investigations on the assessment of CDK4/6 expression in tumors or other tissues. Palbociclib, which was approved in 2015 to treat ER+/HER2-breast cancer in combination with letrozole, is a selective CDK4/6 inhibitor. In this study, an intermediate (compound 3), which could be hydrolyzed into the ligand (compound L) consisting of palbociclib as the bioactive molecule and 6-hydrazino nicotinamide (HYNIC) as the bifunctional chelator, was synthesized. Compound L was radiolabeled with Tc using tricine/TPPTS or tricine/TPPMS as co-ligands. Tc-tricine-TPPTS-L and Tc-tricine-TPPMS-L were prepared with high radiochemical purity without postlabeling purification. They had great in vitro stability. Both radiotracers were hydrophilic, but Tc-tricine-TPPTS-L had a lower log P value. In vitro cell uptake studies in MCF-7 cells showed that cellular uptake was blocked by preincubation with palbociclib, suggesting a CDK4/6-mediated uptake mechanism. Biodistribution in mice bearing MCF-7 tumors showed that Tc-tricine-TPPTS-L had higher tumor uptake than Tc-tricine-TPPMS-L, while they had comparable tumor-to-muscle and tumor-to-blood ratios. Radioactivity accumulation in tumors was obvious in micro-SPECT/CT images with Tc-tricine-TPPTS-L. When mice were preinjected with palbociclib, tumor uptake of Tc-tricine-TPPTS-L significantly decreased and the tumor accumulation was clearly lost, confirming CDK4/6 specificity. All results in this work indicated that Tc-tricine-TPPTS-L is a promising tumor imaging agent that targets CDK4/6.
细胞周期蛋白依赖性激酶 4/6（CDK4/6）的过表达和扩增发生在许多癌症中，可能是临床前模型中 CDK4/6 抑制剂耐药的原因。然而，关于肿瘤或其他组织中 CDK4/6 表达的评估研究较少。帕博西尼于 2015 年被批准与来曲唑联合用于治疗 ER+/HER2-乳腺癌，是一种选择性 CDK4/6 抑制剂。在这项研究中，合成了一种中间体（化合物 3），它可以水解为包含帕博西尼作为生物活性分子和 6-肼基烟酰胺（HYNIC）作为双功能螯合剂的配体（化合物 L）。使用 tricine/TPPTS 或 tricine/TPPMS 作为共配体，用 Tc 标记化合物 L。Tc-tricine-TPPTS-L 和 Tc-tricine-TPPMS-L 无需标记后纯化即可制备出高放射化学纯度。它们具有很好的体外稳定性。两种放射性示踪剂均具有亲水性，但 Tc-tricine-TPPTS-L 的 log P 值较低。在 MCF-7 细胞中的体外细胞摄取研究表明，细胞摄取被 palbociclib 预孵育阻断，表明存在 CDK4/6 介导的摄取机制。在携带 MCF-7 肿瘤的小鼠中的生物分布研究表明，Tc-tricine-TPPTS-L 比 Tc-tricine-TPPMS-L 具有更高的肿瘤摄取率，而它们的肿瘤与肌肉和肿瘤与血液的比率相当。用 Tc-tricine-TPPTS-L 进行 micro-SPECT/CT 成像时，肿瘤中的放射性示踪剂明显积聚。当小鼠预先注射 palbociclib 时，Tc-tricine-TPPTS-L 的肿瘤摄取显著减少，肿瘤积聚明显丢失，证实了 CDK4/6 的特异性。本工作中的所有结果表明，Tc-tricine-TPPTS-L 是一种有前途的靶向 CDK4/6 的肿瘤成像剂。
