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

Chunfeng He ^1,2, Hui Shi ¹, Boyu Tan ^1,3,4

¹State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
²School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
³School of Biomedical Engineering, ShanghaiTech University, Shanghai, 201210, China.
⁴School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
⁵Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Shandong, Yantai, 264117, China.
⁶Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
⁷State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. crqu@simm.ac.cn.
⁸Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. shaoli-song@163.com.
⁹State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. zcheng@simm.ac.cn.
¹⁰School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. zcheng@simm.ac.cn.
¹¹Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Shandong, Yantai, 264117, China. zcheng@simm.ac.cn.

⁰State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

European Journal of Nuclear Medicine and Molecular Imaging +

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July 16, 2024

View abstract on PubMed

Summary

This study developed a novel PET probe, [68Ga]Ga-SMIC-2001, for imaging Poly (ADP-ribose) polymerase (PARP) overexpression in tumors. The probe demonstrates low liver uptake and high tumor-to-background contrast, improving tumor detection in preclinical models.

Area Of Science

Nuclear Medicine
Radiochemistry
Oncology Imaging

Background

Poly (ADP-ribose) polymerase (PARP) overexpression is linked to various diseases, including cancers.
Existing 18F-labeled PARP radiotracers show limitations in hepatic clearance and tumor-to-background ratios.
Developing novel positron emission tomography (PET) probes with improved properties is crucial for effective tumor imaging.

Purpose Of The Study

To design and synthesize a novel PET probe with a low lipid-water partition coefficient for enhanced tumor imaging.
To evaluate the in vitro and in vivo performance of the novel probe for targeting PARP-overexpressing tumors.

Main Methods

A pyridine-containing quinazoline-2,4(1H,3H)-dione PARP-targeting moiety was conjugated with DOTA to create SMIC-2001.
[68Ga]Ga-SMIC-2001 was prepared and characterized for its lipid-water partition coefficient, stability, binding affinity, and cellular uptake.
Tumor imaging properties were assessed in U87MG xenograft models.

Main Results

[68Ga]Ga-SMIC-2001 exhibited a low Log D7.4 (-3.82 ± 0.06) and high affinity for PARP-1 (48.13 nM).
The probe demonstrated high tumor-to-background contrast in U87MG xenografts with predominantly renal clearance.
High tumor-to-organ ratios were observed, with a tumor-to-liver ratio of 2.20 ± 0.51 at 60 min post-injection.

Conclusions

Pyridine-containing quinazoline-2,4(1H,3H)-dione represents a novel molecular scaffold for developing PARP-targeting imaging probes.
[68Ga]Ga-SMIC-2001 is a promising PET probe for imaging tumors with PARP overexpression.
The probe's favorable pharmacokinetic profile suggests potential for improved clinical tumor detection.

Keywords:

Oncology PARP PET/CT Quinazoline-2,4(1H,3H)-dione