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

• Published in: European journal of nuclear medicine and molecular imaging 2023-06, Vol.50 (7), p.2081-2099
• Main Authors: Chen, Baosheng, Ojha, Devi Prasan, Toyonaga, Takuya, Tong, Jie, Pracitto, Richard, Thomas, Monique A., Liu, Michael, Kapinos, Michael, Zhang, Li, Zheng, Ming-Qiang, Holden, Daniel, Fowles, Krista, Ropchan, Jim, Nabulsi, Nabeel, De Feyter, Henk, Carson, Richard E., Huang, Yiyun, Cai, Zhengxin
• Format: Article
• Language: English
• Subjects: Animals; Binding; Biodistribution; Brain; Brain - diagnostic imaging; Brain - metabolism; Brain cancer; Cardiology; Clinical trials; Glioblastoma; Glioblastoma - diagnostic imaging; Glioblastoma - metabolism; Imaging; Imidazole; Immunoblotting; Immunohistochemistry; In vivo methods and tests; Kinetics; Medical imaging; Medicine; Medicine & Public Health; Monkeys; Neuroimaging; Nuclear Medicine; Oncology; Oncology – Brain; Original Article; Orthopedics; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - metabolism; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Primates; Radiochemistry; Radiology; Rats; Ribose; Synthesis; Tissue Distribution; Tumors
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-023-06162-y

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- 11 C)pyrrolidin-2-yl)-1 H -benzo[ d ]imidazole-4-carboxamide ([ 11 C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates. Methods We synthesized [ 11 C]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 [ 11 C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution ( V T ), nondisplaceable volume of distribution ( V ND ), and nondisplaceable binding potential ( BP ND ) in selected brain regions. Results [ 11 C]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). [ 11 C]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 [ 11 C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake ( BP ND  > 3) and low nonspecific uptake ( V ND