Imaging poly(ADP-ribose) polymerase-1 (PARP1) <i>in vivo</i> with <sup>18</sup>F-labeled brain penetrant positron emission tomography (PET) ligand.

Xin ZHOU; Jiahui CHEN; Jimmy S PATEL; Wenqing RAN; Yinlong LI; Richard S VAN; Mostafa M H IBRAHIM; Chunyu ZHAO; Yabiao GAO; Jian RONG; Ahmad F CHAUDHARY; Guocong LI; Junqi HU; April T DAVENPORT; James B DAUNAIS; Yihan SHAO; Chongzhao RAN; Thomas L COLLIER; Achi HAIDER; David M SCHUSTER; Allan I LEVEY; Lu WANG; Gabriel CORFAS; Steven H LIANG

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Imaging poly(ADP-ribose) polymerase-1 (PARP1) in vivo with ¹⁸F-labeled brain penetrant positron emission tomography (PET) ligand.

Author: Xin ZHOU ¹ ; Jiahui CHEN ¹ ; Jimmy S PATEL ¹ ; Wenqing RAN ² ; Yinlong LI ¹ ; Richard S VAN ³ ; Mostafa M H IBRAHIM ⁴ ; Chunyu ZHAO ¹ ; Yabiao GAO ¹ ; Jian RONG ¹ ; Ahmad F CHAUDHARY ¹ ; Guocong LI ² ; Junqi HU ² ; April T DAVENPORT ⁵ ; James B DAUNAIS ⁶ ; Yihan SHAO ³ ; Chongzhao RAN ⁷ ; Thomas L COLLIER ¹ ; Achi HAIDER ¹ ; David M SCHUSTER ¹ ; Allan I LEVEY ⁸ ; Lu WANG ² ; Gabriel CORFAS ⁴ ; Steven H LIANG ¹
Author Information

1. Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA 30322, USA.
2. Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine & Key Laboratory of Basic and Translational Research on Radiopharmaceuticals, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
3. Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA.
4. Kresge Hearing Research Institute, Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
5. Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA.
6. Department of Internal Medicine, Section on Infectious Diseases, Wake Forest School of Medicine, Winston Salem, NC 27157, USA.
7. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MI 02114, USA.
8. Department of Neurology, Emory University, Atlanta, GA 30322, USA.
Publication Type:Journal Article
Keywords: Cell death; DNA damage; Fluorine 18; Imaging; PARP1; PET; Poly(ADP-ribose) polymerase-1; Positron emission tomography
From: Acta Pharmaceutica Sinica B 2025;15(10):5036-5049
CountryChina
Language:English
Abstract: 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 ¹⁸F-isotopologue ([¹⁸F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and in vivo PET imaging evaluations in non-human primates, demonstrates the capacity of [¹⁸F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [¹⁸F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.

Imaging poly(ADP-ribose) polymerase-1 (PARP1) in vivo with 18F-labeled brain penetrant positron emission tomography (PET) ligand.

Imaging poly(ADP-ribose) polymerase-1 (PARP1) in vivo with ¹⁸F-labeled brain penetrant positron emission tomography (PET) ligand.