目前，有多项活跃的临床试验正在研究使用聚(ADP-核糖)聚合酶（PARP）抑制剂治疗胶质母细胞瘤。利用正电子发射断层扫描技术（PET）对基线PARP表达进行非侵入式定量分析，可提供预后信息并推动更精确的治疗。由于缺乏穿透脑部的PARP成像药物，就脑内PARP进行可靠和准确的体内定量分析仍然是棘手的问题。本文报告了一种穿透脑部的PARP PET示踪剂（R）-2-（2-甲基-1-（甲基-11C）吡咯烷-2-基）-1H-苯并[d]-咪唑-4-羧酰胺 ([11C]PyBic) 的合成及其在同基因RG2大鼠胶质母细胞瘤模型和健康非人灵长类动物中的临床前评估。我们使用维利帕尼作为标记前体合成了[11C]PyBic，对RG2肿瘤鼠进行了动态PET扫描，使用对侧非肿瘤脑区域作为参考区域的简化参考区域法2 (SRTM2) 计算了分布容积比 (DVR)。我们进行了生物分布研究、蛋白质印迹和免疫染色研究，以验证体内PET定量分析结果。我们在FOCUS220扫描仪上对非人类灵长类动物进行了[11C]PyBic的脑动力学和结合特异性的表征，并在选择的脑区域计算了分布量 (VT)、非可替代分布量 (VND) 和非可替代结合势 (BPND)。[11C]PyBic在一步中高效地合成，其放射化学纯度和化学纯度均超过97％，其摩尔活性为148±85 MBq/nmol (n=6)。[11C]PyBic在RG2肿瘤中表现出PARP特异性结合，75％的示踪剂结合被预注射的维利帕尼（i.v.，5mg/kg）阻断。体内PET成像结果与体外生物分布、PARP1免疫组化和免疫印迹数据相一致。此外，猴子脑PET证实了[11C]PyBic的穿透能力，显示出在猴子脑中具有高特异性吸收（BPND>3）和低非特异性吸收（VND<3 mL/cm3）。[11C]PyBic是在大鼠胶质母细胞瘤模型和健康非人类灵长类动物中验证的第一个穿透脑部的PARP PET示踪剂。[11C]PyBic的脑动力学适用于脑内PARP结合的非侵入式定量分析，从而可以广泛应用于癌症和神经影像学。 © 2023年作者，专享授权给Springer-Verlag GmbH Germany，隶属于Springer Nature。

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.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.