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Quinazoline-2,4(1 H,3 H)-dione Scaffold for development of a novel PARP-targeting PET probe for tumor imaging

文献类型：期刊论文

作者He, Chunfeng5,6; Shi, Hui6; Tan, Boyu3,4,6; Jiang, Zhaoning2,5,6; Cao, Rui6; Zhu, Jiamin5,6; Qian, Kun6; Wang, Xiao1; Xu, Xiaoping6; Qu, Chunrong6
刊名EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
出版日期2024-07-16
页码14
关键词PARP Oncology Quinazoline-2,4(1H,3H)-dione PET/CT
ISSN号1619-7070
DOI10.1007/s00259-024-06843-2
通讯作者Qu, Chunrong(crqu@simm.ac.cn) ; Song, Shaoli(shaoli-song@163.com) ; Cheng, Zhen(zcheng@simm.ac.cn)
英文摘要Purpose Overexpression of Poly (ADP-ribose) polymerase (PARP) is associated with many diseases such as oncological diseases. Several PARP-targeting radiotracers have been developed to detect tumor in recent years. Two F-18 labelled probes based on Olaparib and Rucaparib molecular scaffolds have been evaluated in clinical trials, but their slow hepatic clearance hinders their tumor imaging performance. Although a number of positron emission tomography (PET) probes with lower liver uptake have been designed, the tumor to background ratios remains to be low. Therefore, we designed a probe with low lipid-water partition coefficient to solve this problem. Methods A pyridine-containing quinazoline-2,4(1 H,3 H)-dione PARP-targeting group was rationally designed and used to conjugate with the chelator 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) to prepare the lead compound named as SMIC-2001 for radiolabeling. In vitro experiments, the lipid-water partition coefficient, stability, binding affinity, and cellular uptake of [Ga-68]Ga-SMIC-2001 were determined. In vivo experiments, the U87MG xenograft models were used to evaluate its tumor imaging properties. Results [Ga-68]Ga-SMIC-2001 showed a low Log D-7.4 (-3.82 +/- 0.06) and high affinity for PARP-1 (48.13 nM). In vivo study revealed that it exhibited a high tumor-to-background contrast in the U87MG xenograft models and mainly renal clearance. And the ratios of tumor to main organs were high except for the kidney (e.g. tumor to liver ratio reached 2.20 +/- 0.51) at 60 min p.i. Conclusion In summary, pyridine-containing quinazoline-2,4(1 H,3 H)-dione is a novel PARP-targeting molecular scaffold for imaging probe development, and [Ga-68]Ga-SMIC-2001 is a highly promising PET probe capable of imaging tumors with PARP overexpression.
WOS关键词INHIBITORS ; POLYMERASE ; DISCOVERY
资助项目National Natural Science Foundation of China[U2267221] ; Shanghai Municipal Science and Technology Major Project[TM202301H003] ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0120231004] ; Gansu Science and Technology Major Project[23ZDFA014] ; Shandong Laboratory Program[SYS202205] ; Pharmaceutical Technology Co., Ltd. (Suzhou, China)
WOS研究方向Radiology, Nuclear Medicine & Medical Imaging
语种英语
WOS记录号WOS:001269187700001
出版者SPRINGER
源URL[http://119.78.100.183/handle/2S10ELR8/312380]  
专题新药研究国家重点实验室
通讯作者Qu, Chunrong; Song, Shaoli; Cheng, Zhen
作者单位1.Fudan Univ, Shanghai Canc Ctr, Dept Nucl Med, Shanghai 200032, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.ShanghaiTech Univ, Sch Biomed Engn, Shanghai 201210, Peoples R China
5.Univ Chinese Acad Sci, Sch Pharm, 19A Yuquan Rd, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Mol Imaging Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 He, Chunfeng,Shi, Hui,Tan, Boyu,et al. Quinazoline-2,4(1 H,3 H)-dione Scaffold for development of a novel PARP-targeting PET probe for tumor imaging[J]. EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING,2024:14.
APA He, Chunfeng.,Shi, Hui.,Tan, Boyu.,Jiang, Zhaoning.,Cao, Rui.,...&Cheng, Zhen.(2024).Quinazoline-2,4(1 H,3 H)-dione Scaffold for development of a novel PARP-targeting PET probe for tumor imaging.EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING,14.
MLA He, Chunfeng,et al."Quinazoline-2,4(1 H,3 H)-dione Scaffold for development of a novel PARP-targeting PET probe for tumor imaging".EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING (2024):14.

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来源：上海药物研究所

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