背景:前列腺特异性膜抗原(PSMA)PET成像最近在胶质母细胞瘤(GBM)患者中作为PSMA放射性配体治疗的潜在治疗靶点受到关注。然而,PSMAPET尚未在鼠GBM模型中建立。我们的目标是研究同系GL261GBM模型中PSMAPET成像的潜力,并对该模型中PMSA放射性配体治疗的潜力进行展望。
方法:我们在原位GL261模型中进行了18F-PSMA-1007PET研究(n=14GBM,n=7只假手术小鼠),在植入后第4、8、11、15、18和22天进行成像。时间-活性-曲线(TAC)从动态PET扫描(0-120分钟p.i.)中提取小鼠子集(n=4GBM,n=3只假手术小鼠),以确定图像分析的最佳时间范围,在所有小鼠中计算使用对侧正常脑作为背景的标准化摄取值(SUV)以及肿瘤与背景的比率(TBR)。此外,计算机断层扫描(CT),进行离体和体外18F-PSMA-1007放射自显影(ARG)。
结果:对GBM小鼠的TAC分析揭示了40分钟p.i后TBR值的平台。因此,选择在40-70分钟p.i.之间的30分钟时间范围用于PET定量。在第15天及以后,GBM小鼠在接种部位显示出明显的PSMAPET信号,在第18天,GBM小鼠的TBRmean最高(7.3±1.3与1.6±0.3英寸;p=0.024)。与健康背景相比,体外ARG在GBM中证实了高示踪剂信号(TBRmean26.9±10.5vs.植入后第18/22天1.6±0.7英寸;p=0.002)。然而,GL261肿瘤的绝对摄取值仍然很低(例如,在第18天,SUVmean为0.21±0.04g/ml),导致与剂量相关器官相比的比率较低(例如,平均肿瘤肾比值1.5E-2±0.5E-2)。
结论:尽管GL261荷瘤小鼠的18F-PSMA-1007PET成像是可行的,并导致高TBR,绝对肿瘤摄取值仍然很低,提示GL261模型在PSMA定向治疗研究中的适用性有限.有必要进行进一步的研究,以确定合适的模型,用于GBM中PSMA靶向治疗方法的临床前评估。
BACKGROUND: Prostate specific membrane antigen (PSMA) PET imaging has recently gained attention in glioblastoma (GBM) patients as a potential theranostic target for PSMA radioligand therapy. However, PSMA PET has not yet been established in a murine GBM model. Our goal was to investigate the potential of PSMA PET imaging in the syngeneic GL261 GBM model and to give an outlook regarding the potential of PMSA radioligand therapy in this model.
METHODS: We performed an 18F-PSMA-1007 PET study in the orthotopic GL261 model (n=14 GBM, n=7 sham-operated mice) with imaging at day 4, 8, 11, 15, 18 and 22 post implantation. Time-activity-curves (TAC) were extracted from dynamic PET scans (0-120 min p. i.) in a subset of mice (n=4 GBM, n=3 sham-operated mice) to identify the optimal time frame for image analysis, and standardized-uptake-values (SUV) as well as tumor-to-background ratios (TBR) using contralateral normal brain as background were calculated in all mice. Additionally, computed tomography (CT), ex vivo and in vitro 18F-PSMA-1007 autoradiographies (ARG) were performed.
RESULTS: TAC analysis of GBM mice revealed a plateau of TBR values after 40 min p. i. Therefore, a 30 min time frame between 40-70 min p. i. was chosen for PET quantification. At day 15 and later, GBM mice showed a discernible PSMA PET signal on the inoculation site, with highest TBRmean in GBM mice at day 18 (7.3 ± 1.3 vs. 1.6 ± 0.3 in shams; p=0.024). Ex vivo ARG confirmed high tracer signal in GBM compared to healthy background (TBRmean 26.9 ± 10.5 vs. 1.6 ± 0.7 in shams at day 18/22 post implantation; p=0.002). However, absolute uptake values in the GL261 tumor remained low (e.g., SUVmean 0.21 ± 0.04 g/ml at day 18) resulting in low ratios compared to dose-relevant organs (e.g., mean tumor-to-kidney ratio 1.5E-2 ± 0.5E-2).
CONCLUSIONS: Although 18F-PSMA-1007 PET imaging of GL261 tumor-bearing mice is feasible and resulted in high TBRs, absolute tumoral uptake values remained low and hint to limited applicability of the GL261 model for PSMA-directed therapy studies. Further investigations are warranted to identify suitable models for preclinical evaluation of PSMA-targeted theranostic approaches in GBM.