Imaging poly(ADP-ribose) polymerase-1 (PARP1) in vivo with 18F-labeled brain penetrant positron emission tomography (PET) ligand
Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies. Despite the increased use of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) radioligand is crucial for understanding disease biology and performing target occupancy studies, which may aid in the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its <sup>18</sup>F-isotopologue ([<sup>18</sup>F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and <i>in vivo</i> PET imaging evaluations in non-human primates, demonstrates the capacity of [<sup>18</sup>F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [<sup>18</sup>F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.
Authors
- Yihan Shao (ORCID: https://orcid.org/0000-0001-9337-341X)
- Steven H. Liang (ORCID: https://orcid.org/0000-0003-1413-6315)
- Mostafa M.H. Ibrahim (ORCID: https://orcid.org/0000-0003-2038-9933)
- Allan I. Levey (ORCID: https://orcid.org/0000-0002-3153-502X)
- Chunyu Zhao (ORCID: https://orcid.org/0000-0003-0168-2130)
- Xin Zhou (ORCID: https://orcid.org/0000-0002-7444-462X)
- David M. Schuster (ORCID: https://orcid.org/0000-0003-3077-742X)
- Yinlong Li (ORCID: https://orcid.org/0000-0002-8864-1712)
- Wenqing Ran
- Guocong Li
- Lu Wang (ORCID: https://orcid.org/0000-0002-8049-1991)
- Thomas Collier (ORCID: https://orcid.org/0000-0002-3757-4855)
- Gabriel Corfas (ORCID: https://orcid.org/0000-0001-5412-9473)
- Chongzhao Ran (ORCID: https://orcid.org/0000-0002-3892-4108)
- April T. Davenport (ORCID: https://orcid.org/0000-0002-9005-0487)
- Richard Van (ORCID: https://orcid.org/0000-0002-0185-9277)
- Jiahui Chen (ORCID: https://orcid.org/0000-0001-9186-1110)
- Jian Rong (ORCID: https://orcid.org/0000-0002-3960-1669)
- Jimmy S. Patel (ORCID: https://orcid.org/0000-0002-7322-7578)
- Yabiao Gao (ORCID: https://orcid.org/0000-0001-7600-9982)
- Ahmed Haider (ORCID: https://orcid.org/0000-0002-5204-4473)
- Ahmad Chaudhary (ORCID: https://orcid.org/0009-0007-0614-3335)
- James B. Daunais
- Junqi Hu
Institutions
- Emory University (US)
- University of Michigan (US)
- Athinoula A. Martinos Center for Biomedical Imaging (US)
- First Affiliated Hospital of Jinan University (CN)
- Wake Forest University (US)
- University of Oklahoma (US)
Publication Details
- Journal
- Acta Pharmaceutica Sinica B
- Published
- 2025-05-26
- DOI
- https://doi.org/10.1016/j.apsb.2025.05.020
- Citations
- 12
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 12.54
Funders
- Foundation for the National Institutes of Health
- National Institutes of Health
- National Cancer Institute