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Preclinical evaluation of a brain penetrant PARP PET imaging probe in rat glioblastoma and nonhuman primates

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive. Herein, we report the synthesis of a brain-penetrant PARP PET tracer, (R)-2-(2-methyl-1-(methyl-11C)pyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide ([11C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates.

Methods

We synthesized [11C]PyBic using veliparib as the labeling precursor, performed dynamic PET scans on RG2 tumor-bearing rats and calculated the distribution volume ratio (DVR) using simplified reference region method 2 (SRTM2) with the contralateral nontumor brain region as the reference region. We performed biodistribution studies, western blot, and immunostaining studies to validate the in vivo PET quantification results. We characterized the brain kinetics and binding specificity of [11C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution (VT), nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND) in selected brain regions.

Results

[11C]PyBic was synthesized efficiently in one step, with greater than 97% radiochemical and chemical purity and molar activity of 148 ± 85 MBq/nmol (n = 6). [11C]PyBic demonstrated PARP-specific binding in RG2 tumors, with 74% of tracer binding in tumors blocked by preinjected veliparib (i.v., 5 mg/kg). The in vivo PET imaging results were corroborated by ex vivo biodistribution, PARP1 immunohistochemistry and immunoblotting data. Furthermore, brain penetration of [11C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake (BPND > 3) and low nonspecific uptake (VND < 3 mL/cm3) in the monkey brain.

Conclusion

[11C]PyBic is the first brain-penetrant PARP PET tracer validated in a rat glioblastoma model and healthy nonhuman primates. The brain kinetics of [11C]PyBic are suitable for noninvasive quantification of available PARP binding in the brain, which posits [11C]PyBic to have broad applications in oncology and neuroimaging.

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Data availability

Imaging data are available upon reasonable request to the corresponding author.

Abbreviations

BBB:

Blood brain barrier

PARP:

Poly (ADP-ribose) polymerase

GBM:

Glioblastoma multiforme

SUV:

Standardized uptake value

TAC:

Time activity curve

RCY:

Radiochemical yield

PDB:

Protein database

HPLC:

High-performance liquid chromatography

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Acknowledgements

The authors appreciate the staff at the Yale PET Center for their technical assistance and would like to thank Andrew Gifford, Sarah J. Routledge, and Kiran Shabir for their technical support in the binding assays.

Funding

This study is supported by the National Cancer Institute of the National Institutes of Health under Award Number R03CA249569. This publication was made possible by CTSA grant UL1 RR024139 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Author notes

  1. Baosheng Chen, Devi Prasan Ojha, Takuya Toyonaga, Jie Tong are authors contributed equally.

Authors and Affiliations

  1. Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT, 06520-8048, USA

    Baosheng Chen, Devi Prasan Ojha, Takuya Toyonaga, Jie Tong, Richard Pracitto, Michael Liu, Michael Kapinos, Li Zhang, Ming-Qiang Zheng, Daniel Holden, Krista Fowles, Jim Ropchan, Nabeel Nabulsi, Richard E. Carson, Yiyun Huang & Zhengxin Cai

  2. Magnetic Resonance Research Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA

    Monique A. Thomas & Henk De Feyter

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  1. Baosheng Chen
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Contributions

D.O., R.P., J.T., J.R., Y.H., Z.C. contributed to the design and synthesis of the radioligand. B.C., T.T., M.L., M.T., D.H., K.F., H.D.F., R.E.C. contributed to the animal imaging and ex vivo and in vitro validation studies. M.K., L.Z., and M.Q.Z. performed the metabolism analysis. H.D.F. acquired MRI data and analyzed tumor volumes. R.E.C. and Y.H. supervised the PET imaging study. B.C., D.O., Z.C. drafted the article. Z.C. conceived and supervised the whole study. All authors contributed to the final version of the manuscript.

Corresponding author

Correspondence to Zhengxin Cai.

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PET imaging experiments were performed in rats and rhesus monkeys (Macaca mulatta) according to the protocols approved by the Yale University Institutional Animal Care and Use Committee. All applicable international, national, and institutional guidelines for the care and use of animals were followed.

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Chen, B., Ojha, D.P., Toyonaga, T. et al. Preclinical evaluation of a brain penetrant PARP PET imaging probe in rat glioblastoma and nonhuman primates. Eur J Nucl Med Mol Imaging 50, 2081–2099 (2023). https://doi.org/10.1007/s00259-023-06162-y

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