Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Research site Leipzig, Leipzig, Germany.
Department of Research and Development, ROTOP Pharmaka GmbH, Dresden, Germany.
Eur J Nucl Med Mol Imaging. 2024 Mar;51(4):1085-1096. doi: 10.1007/s00259-023-06515-7. Epub 2023 Nov 20.
Glioma are clinically challenging tumors due to their location and invasiveness nature, which often hinder complete surgical resection. The evaluation of the isocitrate dehydrogenase mutation status has become crucial for effective patient stratification. Through a transdisciplinary approach, we have developed an F-labeled ligand for non-invasive assessment of the IDH1R132H variant by using positron emission tomography (PET) imaging. In this study, we have successfully prepared diastereomerically pure [F]AG-120 by copper-mediated radiofluorination of the stannyl precursor 6 on a TRACERlab FX2 N radiosynthesis module. In vitro internalization studies demonstrated significantly higher uptake of [F]AG-120 in U251 human high-grade glioma cells with stable overexpression of mutant IDH1 (IDH1R132H) compared to their wild-type IDH1 counterpart (0.4 vs. 0.013% applied dose/µg protein at 120 min). In vivo studies conducted in mice, exhibited the excellent metabolic stability of [F]AG-120, with parent fractions of 85% and 91% in plasma and brain at 30 min p.i., respectively. Dynamic PET studies with [F]AG-120 in naïve mice and orthotopic glioma rat model reveal limited blood-brain barrier permeation along with a low uptake in the brain tumor. Interestingly, there was no significant difference in uptake between mutant IDH1R132H and wild-type IDH1 tumors (tumor-to-blood ratio: ~1.7 vs. ~1.3). In conclusion, our preclinical evaluation demonstrated a target-specific internalization of [F]AG-120 in vitro, a high metabolic stability in vivo in mice, and a slightly higher accumulation of activity in IDH1R132H-glioma compared to IDH1-glioma. Overall, our findings contribute to advancing the field of molecular imaging and encourage the evaluation of [F]AG-120 to improve diagnosis and management of glioma and other IDH1R132H-related tumors.
由于位置和侵袭性，神经胶质瘤是临床上具有挑战性的肿瘤，这往往阻碍了完全的手术切除。异柠檬酸脱氢酶突变状态的评估对于有效的患者分层变得至关重要。通过跨学科的方法，我们已经开发了一种 F 标记的配体，用于通过正电子发射断层扫描（PET）成像对 IDH1R132H 变体进行非侵入性评估。在这项研究中，我们已经成功地在 TRACERlab FX2 N 放射性合成模块上通过铜介导的锡前体 6 的放射性氟标记制备了非对映异构体纯的[F]AG-120。体外内化研究表明，与野生型 IDH1 （IDH1R132H）相比，具有稳定过表达突变 IDH1 （IDH1R132H）的 U251 人高级别神经胶质瘤细胞对[F]AG-120 的摄取明显更高（120 分钟时为 0.4%与 0.013%应用剂量/μg 蛋白）。在小鼠体内研究中，在 30 分钟时，[F]AG-120 在血浆和大脑中的母体分数分别为 85%和 91%，表现出良好的代谢稳定性。在未经处理的小鼠和原位神经胶质瘤大鼠模型中进行的动态 PET 研究显示，血脑屏障渗透有限，脑肿瘤摄取量低。有趣的是，突变型 IDH1R132H 和野生型 IDH1 肿瘤之间的摄取没有显著差异（肿瘤与血液的比率：1.7 比1.3）。总之，我们的临床前评估表明，[F]AG-120 在体外具有特异性的靶内摄取，在小鼠体内具有高代谢稳定性，与 IDH1 神经胶质瘤相比，IDH1R132H 神经胶质瘤的活性积累略高。总体而言，我们的研究结果为分子成像领域的发展做出了贡献，并鼓励评估[F]AG-120 以改善神经胶质瘤和其他 IDH1R132H 相关肿瘤的诊断和管理。
