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Lipophilicity-Optimized PARP-1 Tracers: Minimizing Hepatic Retention for Enhanced Target-to-Background PET Imaging
Yi Xie1,2, Chongchong Gao3, Hualong Chen1
1Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, China.
Molecular Pharmaceutics
|October 8, 2025
Summary
Researchers developed new PET tracers targeting PARP-1 by optimizing lipophilicity and adding targeting molecules. The tracer [68Ga]1c showed improved tumor uptake and contrast, showing promise for clinical use in cancer imaging.
Area of Science:
- Radiochemistry
- Molecular Imaging
- Oncology
Background:
- Developing effective PET tracers for Poly(ADP-ribose) polymerase 1 (PARP-1) is crucial for cancer imaging.
- Achieving high tumor-to-background contrast with PARP-1 tracers remains a significant challenge.
Purpose of the Study:
- To design and synthesize novel 68Ga or 18F-labeled Olaparib derivatives as PARP-1 targeted PET tracers.
- To optimize tracer performance by modulating lipophilicity and incorporating active targeting moieties.
- To evaluate the diagnostic potential of these tracers for PARP-1-expressing tumors.
Main Methods:
- Synthesis and radiolabeling of Olaparib derivatives with 68Ga or 18F.
- In vitro and in vivo evaluation of radiotracers in cancer models.
- Assessment of tumor uptake, retention, biodistribution, and target specificity through PET imaging and blocking studies.
Main Results:
- [68Ga]1c, with a hydrophilic DODAGA chelator, exhibited superior tumor uptake and retention compared to [68Ga]DOTA-Olaparib.
- This tracer demonstrated significantly improved tumor-to-muscle and tumor-to-liver ratios in subcutaneous tumor models.
- Amino acid-modified and PEGylated derivatives showed reduced performance, indicating sensitivity to molecular modifications.
Conclusions:
- The dual-path optimization strategy effectively enhanced PARP-1 tracer performance.
- [68Ga]1c shows significant promise for clinical translation in PARP-1 targeted cancer imaging.
- Balancing hydrophilicity and molecular size is critical for designing effective PARP-1 PET tracers.
