Preclinical Evaluation of Itareparib, a brain penetrant PARP1-selective radioligand, in Glioma Rat Model and Nonhuman Primate
Abstract
Rationale: Poly(ADP-ribose) polymerase-1 (PARP1) is a central mediator of DNA damage response and is upregulated in glioma, supporting it as a molecular imaging biomarker. However, quantitative PET assessment of PARP1 in infiltrative tumors with a preserved blood-brain barrier remains an unmet need. In this study, we evaluated if [18F]Itareparib, a brain-penetrant, non-trapping, PARP1-selective radioligand with reversible kinetics, could improve brain tumor diagnosis and enable target occupancy studies in neurooncology. Methods: [18F]Itareparib was synthesized and evaluated in an orthotopic rat model of BT142 IDH1-mutant gliomas. Dynamic PET scans were performed with or without the administration of the PARP1-selective inhibitor AZD9574. Standardized uptake value ratios (SUVRs) for tumors were calculated using the contralateral region as reference and compared with distribution volume ratios (DVRs) calculated using kinetic modeling. PARP1-specific binding and tracer stability were assessed using autoradiography, immunofluorescence, biodistribution, and radiometabolite analysis. Brain kinetics of [18F]Itareparib were evaluated in a healthy nonhuman primate (NHP) at baseline and blocking conditions. Results: [18F]Itareparib rapidly entered the rat brains and showed 4-fold higher uptake in BT142 tumors than in the contralateral brain. AZD9574 reduced tumor uptake by 77%, supporting the PARP1-specific binding of [18F]Itareparib in the tumors. SUVR(30-60 min) showed the closest agreement with DVR. Autoradiographic tumor-to-reference mean ratio was 7.3, and AZD9574 reduced the tumor-to-reference ratio by 56%. PARP1 immunofluorescence was higher in tumor than the rest of the brain and correlated with autoradiographic results. In rats, the parent fraction of [18F]Itareparib exceeded 99% in brain through 60 min post tracer injection (p.i.) and was approximately 88% in plasma at 60 min p.i. In the NHP, [18F]Itareparib showed rapid brain uptake, and VT decreased by 21+/-6 % after blocking with AZD9574. Conclusion: [18F]Itareparib showed brain penetration, high in vivo metabolic stability, reversible binding kinetics, and PARP1-specific tumor uptake. These findings support further development of [18F]Itareparib for the quantitative PET imaging of PARP1 in brain tumors.
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BibTeX
@misc{tan2026preclinical,
title = {{Preclinical Evaluation of Itareparib, a brain penetrant PARP1-selective radioligand, in Glioma Rat Model and Nonhuman Primate}},
author = {Peng Wen Tan and Nira Hernandez-Martin and Claudia Esposito-Zapero and Christina Sun and Takuya Toyonaga and Ming-Ǫiang Zheng and Michael Kapinos and Monique A Thomas and Syed Faraz Nejati and Clement Korsah and Daniel Holden and Baosheng Chen and Jorge Sepulcre and Richard E. Carson and Yiyun Huang and Henk M. De Feyter and Zhengxin Cai},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.758050},
url = {https://www.biorxiv.org/content/10.64898/2026.10.16.758050v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Preclinical Evaluation of Itareparib, a brain penetrant PARP1-selective radioligand, in Glioma Rat Model and Nonhuman Primate
AU - Peng Wen Tan
AU - Nira Hernandez-Martin
AU - Claudia Esposito-Zapero
AU - Christina Sun
AU - Takuya Toyonaga
AU - Ming-Ǫiang Zheng
AU - Michael Kapinos
AU - Monique A Thomas
AU - Syed Faraz Nejati
AU - Clement Korsah
AU - Daniel Holden
AU - Baosheng Chen
AU - Jorge Sepulcre
AU - Richard E. Carson
AU - Yiyun Huang
AU - Henk M. De Feyter
AU - Zhengxin Cai
PY - 2026
DA - 2026/10/16
PB - bioRxiv
DO - 10.64898/2026.10.16.758050
UR - https://www.biorxiv.org/content/10.64898/2026.10.16.758050v1
AB - Rationale: Poly(ADP-ribose) polymerase-1 (PARP1) is a central mediator of DNA damage response and is upregulated in glioma, supporting it as a molecular imaging biomarker. However, quantitative PET assessment of PARP1 in infiltrative tumors with a preserved blood-brain barrier remains an unmet need. In this study, we evaluated if [18F]Itareparib, a brain-penetrant, non-trapping, PARP1-selective radioligand with reversible kinetics, could improve brain tumor diagnosis and enable target occupancy studies in neurooncology. Methods: [18F]Itareparib was synthesized and evaluated in an orthotopic rat model of BT142 IDH1-mutant gliomas. Dynamic PET scans were performed with or without the administration of the PARP1-selective inhibitor AZD9574. Standardized uptake value ratios (SUVRs) for tumors were calculated using the contralateral region as reference and compared with distribution volume ratios (DVRs) calculated using kinetic modeling. PARP1-specific binding and tracer stability were assessed using autoradiography, immunofluorescence, biodistribution, and radiometabolite analysis. Brain kinetics of [18F]Itareparib were evaluated in a healthy nonhuman primate (NHP) at baseline and blocking conditions. Results: [18F]Itareparib rapidly entered the rat brains and showed 4-fold higher uptake in BT142 tumors than in the contralateral brain. AZD9574 reduced tumor uptake by 77%, supporting the PARP1-specific binding of [18F]Itareparib in the tumors. SUVR(30-60 min) showed the closest agreement with DVR. Autoradiographic tumor-to-reference mean ratio was 7.3, and AZD9574 reduced the tumor-to-reference ratio by 56%. PARP1 immunofluorescence was higher in tumor than the rest of the brain and correlated with autoradiographic results. In rats, the parent fraction of [18F]Itareparib exceeded 99% in brain through 60 min post tracer injection (p.i.) and was approximately 88% in plasma at 60 min p.i. In the NHP, [18F]Itareparib showed rapid brain uptake, and VT decreased by 21+/-6 % after blocking with AZD9574. Conclusion: [18F]Itareparib showed brain penetration, high in vivo metabolic stability, reversible binding kinetics, and PARP1-specific tumor uptake. These findings support further development of [18F]Itareparib for the quantitative PET imaging of PARP1 in brain tumors.
SN - 2692-8205
ER -