Structure-guided olaparib PET probe enables enhanced PARP-1 precision imaging

Area of Science:

• Oncology
• Radiochemistry
• Molecular Imaging

Background:

• Poly (ADP-ribose) polymerase 1 (PARP-1) imaging is crucial for cancer therapy selection and monitoring.
• Current PARP-1 radiotracers have limitations including low tumor uptake and poor imaging contrast.

Purpose of the Study:

• To develop novel, improved positron emission tomography (PET) probes for PARP-1 imaging.
• To overcome the limitations of existing lipophilic PARP-1 radiotracers.

Main Methods:

• Designed and synthesized novel [18F]AlF-labeled dimeric PET probes based on the olaparib pharmacophore.
• Utilized a multivalency strategy with PEGylation to enhance probe properties.
• Evaluated probe performance including lipophilicity, binding affinity, tumor uptake, and tumor-to-background ratios.

Main Results:

• The dimeric probe [18F]AlF-NOTA-L3 demonstrated significantly reduced lipophilicity (log P = -2.33) and high binding affinity (KD = 75.2 nM).
• [18F]AlF-NOTA-L3 exhibited superior tumor uptake and tumor-to-muscle ratios compared to the monomeric probe.
• Markedly improved tumor-to-background contrast was observed with the dimeric probe.

Conclusions:

• [18F]AlF-NOTA-L3 represents a promising PET imaging agent for PARP-1.
• The developed probe offers enhanced diagnostic utility and accuracy for clinical oncology.
• This study highlights the potential of multivalency and PEGylation strategies for improving PET tracer development.