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[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging
Florian Guibbal1,2, Samantha L Hopkins1, Anna Pacelli1
1Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building , Off Roosevelt Drive, Oxford, OX3 7LJ, UK.
Background:
Poly (ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1-3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP3, and to investigate its potential for PARP targeting in vivo.
Methods:
Using the Cu-mediated 18F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the 18F-labelled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [18F]AZD2461 in vitro was assessed in a range of pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP expression and in vivo in xenograft-bearing mice. Blocking experiments were performed with both olaparib and AZD2461.
Results:
[18F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9 % ± 3 % and 3 % ± 1 % activity yields non-decay corrected). [18F]AZD2461 was taken up in vivo in PARP1-expressing tumours, and the highest uptake was observed for PSN-1 cells (7.34 ± 1.16 %ID/g). In vitro blocking experiments showed a lesser ability of olaparib to reduce [18F]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461.
Conclusion:
Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents.
Insights
This study introduces [18F]AZD2461, a novel radiotracer for Poly (ADP-ribose) polymerase (PARP) imaging. It demonstrates effective tumor uptake and highlights the importance of assessing PARP inhibitor selectivity for PET imaging agents.
Area of Science:
- Radiochemistry and Nuclear Medicine
- Oncology and Cancer Therapeutics
- Molecular Imaging
Background:
- Poly (ADP-ribose) polymerase (PARP) inhibitors are crucial anti-cancer agents.
- Existing radiotracers often target PARP1-3 with high affinity.
- AZD2461, a PARP inhibitor with lower PARP3 affinity, presents a novel target for in vivo investigation.
Purpose of the Study:
- To develop and evaluate [18F]AZD2461 as a PET imaging agent for PARP targeting.
- To assess the in vitro and in vivo characteristics of [18F]AZD2461.
- To investigate the selectivity profile of AZD2461 compared to olaparib.
Main Methods:
- 18F-labelled AZD2461 ([18F]AZD2461) was synthesized using Cu-mediated 18F-fluorodeboronation.
- In vitro cell uptake studies were conducted in pancreatic cancer cell lines.
- In vivo tumor uptake and blocking experiments with olaparib and AZD2461 were performed in xenograft models.
Main Results:
- Efficient radiolabelling of [18F]AZD2461 was achieved through manual and automated methods.
- [18F]AZD2461 showed significant uptake in PARP1-expressing tumors, particularly in PSN-1 xenografts.
- Blocking experiments indicated that olaparib had a reduced ability to displace [18F]AZD2461 binding, suggesting different selectivity.
Conclusions:
- [18F]AZD2461 is a viable PET imaging agent for targeting PARP.
- The study underscores the necessity of evaluating the PARP selectivity profile of radiolabelled PARP inhibitors.
- Understanding selectivity is critical for the accurate application of PET imaging agents in cancer research and therapy.
