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

软膜 结合势 体内分布 正电子发射断层摄影术 体内 核医学 医学 脑瘤 病理 化学 聚ADP核糖聚合酶 癌症研究 药理学 生物 生物化学 聚合酶 生物技术 基因
作者
Baosheng Chen,Devi Prasan Ojha,Takuya Toyonaga,Jie Tong,Richard Pracitto,Monique Thomas,Mengmeng Liu,Michael Kapinos,Li Zhang,Ming-Qiang Zheng,Daniel Holden,Krista Fowles,Jim Ropchan,Nabeel Nabulsi,Henk De Feyter,Richard E. Carson,Yiyun Huang,Zhengxin Cai
出处
期刊:European Journal of Nuclear Medicine and Molecular Imaging [Springer Nature]
卷期号:50 (7): 2081-2099
标识
DOI:10.1007/s00259-023-06162-y
摘要

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.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.[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.[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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