基于CDK4/6靶点的新型肿瘤分子探针的构建与显像研究

Targeted tumor molecular probes are hot spots in the field of current radiopharmaceuticals. As for cyclin dependent kinases 4/6(CDK4/6), they are a class of important kinases for regulating cell cycle progression. The activities of CDK4/6 are often upregulated in many kinds of tumors, thus making them key targets for the development of anticancer drugs. CDK4/6 inhibitors can selectively inhibit CDK4/6, so the construction of novel radiolabeled CDK4/6 inhibitors as tumor molecular probes is feasible and has important significance. Considering palbociclib is currently the only approved CDK4/6 inhibitor on the market, this project expects to obtain novel SPECT/PET tumor molecular probes for targeting CDK4/6 by taking CDK4/6 as the targets, reserving the pharmacophore of palbociclib, choosing the most commonly used radionuclides( 99mTc and 18F) to be labeling nuclides, and using ligand structure modification and labeling strategy optimization. The proposed molecular probes will play an important role in the early diagnosis of tumor, personalized therapy and the monitoring of therapy efficiency of targeted therapy with CDK4/6 inhibitors. The project thinks highly of the combination of originality and practicality and it has important scientific significance and good prospects for application.

靶向性肿瘤分子探针是当今放射性药物的研究热点。就细胞周期蛋白依赖性激酶4/6 (CDK4/6)而言，CDK4/6是细胞周期调节的一类重要激酶，因其在多种肿瘤中活性增强，成为抗肿瘤药物研发的关键靶点。CDK4/6抑制剂能与CDK4/6特异性结合发挥抑制作用，因此围绕CDK4/6抑制剂来构建新型放射性核素标记肿瘤分子探针具有可行性和重要意义。考虑到Palbociclib是目前唯一被批准上市的CDK4/6抑制剂，本项目在保留Palbociclib药效团的基础上，以CDK4/6为靶点，选择临床最常用的99mTc和18F作为标记核素，通过配体结构修饰和标记策略优化以期获得靶向CDK4/6的新型SPECT/PET肿瘤分子探针。该类分子探针将在肿瘤早期诊断、个性化治疗以及CDK4/6抑制剂靶向治疗的疗效监测方面发挥重要作用。项目注重原创性与实用性的结合，具有重要的科学意义和良好的应用前景。

靶向性肿瘤分子探针是当今放射性药物的研究热点。细胞周期蛋白依赖性激酶4/6 (CDK4/6)是细胞周期调节的一类重要激酶，因其在多种肿瘤中活性增强，成为抗肿瘤药物研发的关键靶点。CDK4/6抑制剂能与CDK4/6特异性结合发挥抑制作用，因此围绕CDK4/6抑制剂来构建新型放射性核素标记肿瘤分子探针具有可行性和重要意义。本项目拟制备99mTc和18F标记的Palbociclib衍生物用作靶向CDK4/6的新型SPECT/PET肿瘤分子探针，主要进行了Palbociclib衍生物配体的合成、放射化学标记研究、 放射性标记物的理化性质测定、放射性标记物的结构测定、体内稳定性实验和代谢实验、配合物与肿瘤细胞结合实验和抑制实验、配合物在荷瘤动物的生物分布实验和SPECT/PET显像研究等。成功合成得到6种新型Palbociclib衍生物配体，用99mTc和18F标记后所制备的放射性标记配合物(99mTc-L2, 99mTc-L3, 99mTc-L4, 99mTc-L5, [Al18F]-NOTA-Pab,99mTc-tricine-TPPTS-L, 99mTc-tricine-TPPMS-L)放射化学纯度高且体外稳定性良好。除了99mTc-tricine-TPPTS-L和99mTc-tricine-TPPMS-L配合物显示亲水性，其余5种配合物均为亲脂性物质。体外细胞实验结果表明，所有放射性标记配合物在MCF-7细胞中均有一定摄取，且摄取可以被帕博西尼显著抑制，说明其在MCF-7细胞中的摄取是CDK4/6特异性的。荷MCF-7肿瘤Balb/c裸鼠体内生物分布实验和抑制实验结果表明其在肿瘤中的摄取是CDK4/6特异性的。99mTc-L4 和99mTc-tricine-TPPTS-L的肿瘤SPECT显像和[Al18F]-NOTA-Pab的肿瘤PET显像结果表明其具有较高的肿瘤摄取以及与CDK4/6的特异性结合，具有成为新型靶向CDK4/6肿瘤显像剂的潜力，值得进一步研究。本项目成果促进了新型靶向CDK4/6肿瘤显像剂的研究进程，具有重要的科学意义。

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