Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Shanghai 200032, China.
Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Shanghai 200032, China; Institute of Nuclear Medicine, Fudan University, Shanghai, China; Shanghai Institute of Medical Imaging, Shanghai, China.
Bioorg Med Chem. 2022 Jan 1;53:116525. doi: 10.1016/j.bmc.2021.116525. Epub 2021 Nov 27.
Mutations in isocitrate dehydrogenase 1 (IDH1) are commonly found in various human malignancies. Inhibitors of several mutant IDH1 enzymes have entered clinical trials as target therapeutic drugs for the treatment of patients with IDH1 mutations. Herein, we report the synthesis and evaluation of two F-labeled tracers, [F]AG120 and [F]AG135 for imaging expression of mutated IDH1 in positron emission tomography (PET). [F]AG120 and [F]AG135 were synthesized in decay-corrected radiochemical yield of 1 % and 3 %, respectively, high molar activity (52-66 MBq/nmol and 216-339 MBq/nmol, respectively) and high radiochemical purity (>99%). Both tracers showed good in vitro stability, selective uptake into mutated IDH1-expressing cells and good pharmacokinetic profiles with low uptake in most organs/tissues. Furthermore, [F]AG120 micro-PET/CT imaging displayed significantly greater uptake in IDH1-mutant than in wild-type tumors, Relatively, uptake of [F]AG135 was observed neither in IDH1-mutant tumor xenografts nor in wild-type tumors. This study suggests that [F]AG120 is a promising radiotracer for PET imaging of IDH1 mutation, However, further optimization and investigation are necessary for [F]AG135 due to the limited uptake in mutated IDH1-expressing tumors.
异柠檬酸脱氢酶 1（IDH1）突变常见于多种人类恶性肿瘤中。几种突变 IDH1 酶的抑制剂已进入临床试验，作为治疗 IDH1 突变患者的靶向治疗药物。在此，我们报告了两种 F 标记示踪剂 [F]AG120 和 [F]AG135 的合成和评价，用于正电子发射断层扫描（PET）中突变 IDH1 的表达成像。[F]AG120 和 [F]AG135 的放射性化学产率分别为 1%和 3%，高比活度（分别为 52-66 MBq/nmol 和 216-339 MBq/nmol）和高放射化学纯度（>99%）。两种示踪剂均表现出良好的体外稳定性，对表达突变 IDH1 的细胞具有选择性摄取，并且具有良好的药代动力学特征，大多数器官/组织摄取较低。此外，[F]AG120 微 PET/CT 成像显示在 IDH1 突变肿瘤中的摄取明显大于野生型肿瘤，相比之下，[F]AG135 在 IDH1 突变肿瘤异种移植瘤和野生型肿瘤中均无摄取。本研究表明，[F]AG120 是一种很有前途的用于 IDH1 突变 PET 成像的放射性示踪剂，然而，由于在表达突变 IDH1 的肿瘤中摄取有限，[F]AG135 还需要进一步优化和研究。
