Work

Preclinical Evaluation of [ 18 F]Itareparib, a brain penetrant PARP1-selective radioligand, in Glioma Rat Model and Nonhuman Primate

Year: 2026

Type: preprint

Abstract: 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 [ 18 F]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 [ 18 F]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 [ 18 F]Itareparib were evaluated in a healthy nonhuman primate (NHP) at baseline and blocking conditions. Results [ 18 F]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 [ 18 F]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 [ 18 F]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, [ 18 F]Itareparib showed rapid brain uptake, and V T decreased by 21 ± 6 % after blocking with AZD9574. Conclusion [ 18 F]Itareparib showed brain penetration, high in vivo metabolic stability, reversible binding kinetics, and PARP1-specific tumor uptake. These findings support further development of [ 18 F]Itareparib for the quantitative PET imaging of PARP1 in brain tumors.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.16.758050