Wang Qianna, Feng Junhong, Jiang Yuhao, Ruan Qing, Yin Guangxing, Han Peiwen, Zhang Junbo
Key Laboratory of Radiopharmaceuticals of the Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China.
Department of Isotopes, China Institute of Atomic Energy, P.O. Box 2108, Beijing 102413, P. R. China.
Mol Pharm. 2025 Feb 3;22(2):1010-1019. doi: 10.1021/acs.molpharmaceut.4c01237. Epub 2025 Jan 8.
As an enzyme that plays an important role in DNA repair, poly(ADP-ribose) polymerase-1 (PARP-1) has become a popular target for cancer therapy. Nuclear medicine molecular imaging technology, supplemented by radiolabeled PARP-1 inhibitors, can accurately determine the expression level of PARP-1 at lesion sites to help patients choose an appropriate treatment plan. In this work, niraparib was modified with a hydrazinonicotinamide (HYNIC) group to generate the ligand NPBHYNIC, which has an affinity (IC) of 450.90 nM for PARP-1. The ligand NPBHYNIC was labeled with technetium-99m and six different coligands to yield [Tc]Tc-(/tricine)-NPBHYNIC ( = TPPTS, TPPMS, PSA, PDA, NIC and ISONIC). These complexes were hydrophilic and exhibited good stability , and low levels of these complexes were taken up by nontarget organs and tissues in Kunming mice. Among these complexes, [Tc]Tc-(TPPTS/tricine)-NPBHYNIC and [Tc]Tc-(NIC/tricine)-NPBHYNIC were selected for biodistribution in HeLa tumor-bearing BALB/c nude mice at 2 h post injection. The results revealed that the tumor uptake of [Tc]Tc-(TPPTS/tricine)-NPBHYNIC (1.02 ± 0.07% ID/g) was greater than that of [Tc]Tc-(NIC/tricine)-NPBHYNIC (0.36 ± 0.05% ID/g). Additionally, in biodistribution, single-photon emission computed tomography/computed tomography (SPECT/CT) and radioautography experiments, the tumor uptake of [Tc]Tc-(TPPTS/tricine)-NPBHYNIC was significantly reduced in the blocked group, indicating PARP-1 specificity. Therefore, it has potential for use as a niraparib-based tumor imaging agent that targets PARP-1.
作为一种在DNA修复中起重要作用的酶，聚（ADP - 核糖）聚合酶 -1（PARP -1）已成为癌症治疗的热门靶点。核医学分子成像技术，辅以放射性标记的PARP -1抑制剂，能够准确测定病变部位PARP -1的表达水平，以帮助患者选择合适的治疗方案。在本研究中，用肼基烟酰胺（HYNIC）基团修饰尼拉帕利，生成配体NPBHYNIC，其对PARP -1的亲和力（IC）为450.90 nM。配体NPBHYNIC用99m锝和六种不同的共配体进行标记，得到[Tc]Tc-(/tricine)-NPBHYNIC（ = TPPTS、TPPMS、PSA、PDA、NIC和ISONIC）。这些配合物具有亲水性，表现出良好的稳定性，并且在昆明小鼠体内非靶器官和组织对这些配合物的摄取水平较低。在这些配合物中，选择[Tc]Tc-(TPPTS/tricine)-NPBHYNIC和[Tc]Tc-(NIC/tricine)-NPBHYNIC在注射后2小时对荷HeLa肿瘤的BALB/c裸鼠进行生物分布研究。结果显示，[Tc]Tc-(TPPTS/tricine)-NPBHYNIC的肿瘤摄取率（1.02±0.07% ID/g）高于[Tc]Tc-(NIC/tricine)-NPBHYNIC（0.36±0.05% ID/g）。此外，在生物分布、单光子发射计算机断层扫描/计算机断层扫描（SPECT/CT）和放射自显影实验中，阻断组中[Tc]Tc-(TPPTS/tricine)-NPBHYNIC的肿瘤摄取显著降低，表明其具有PARP -1特异性。因此，它有潜力用作基于尼拉帕利的靶向PARP -1的肿瘤显像剂。
