Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) are commonly found in gliomas. AGI-5198, a potent and selective inhibitor of the mutant IDH1 enzyme, was radiolabeled with radioiodine and fluorine-18. These radiotracers were evaluated as potential probes for imaging mutant IDH1 expression in tumors with positron emission tomography (PET). Radioiodination of AGI-5198 was achieved using a tin precursor in 79 ± 6% yield (n = 9), and ¹⁸F-labeling was accomplished by the Ugi reaction in a decay-corrected radiochemical yield of 2.6 ± 1.6% (n = 5). The inhibitory potency of the analogous nonradioactive compounds against mutant IDH1 (IDH1-R132H) was determined in enzymatic assays. Cell uptake studies using radiolabeled AGI-5198 analogues revealed somewhat higher uptake in IDH1-mutated cells than that in wild-type IDH1 cells. The radiolabeled compounds displayed favorable tissue distribution characteristics in vivo, and good initial uptake in IDH1-mutated tumor xenografts; however, tumor uptake decreased with time. Radioiodinated AGI-5198 exhibited higher tumor-to-background ratios compared with ¹⁸F-labeled AGI-5198; unfortunately, similar results were observed in wild-type IDH1 tumor xenografts as well, indicating lack of selectivity for mutant IDH1 for this tracer. These results suggest that AGI-5198 analogues are not a promising platform for radiotracer development. Nonetheless, insights gained from this study may help in design and optimization of novel chemical scaffolds for developing radiotracers for imaging the mutant IDH1 enzyme.

代谢酶异柠檬酸脱氢酶1（IDH1）的突变通常在神经胶质瘤中发现。AGI-5198是突变IDH1酶的有效和选择性抑制剂，已用放射性碘和氟18进行了放射性标记。这些放射示踪剂被评估为通过正电子发射断层扫描（PET）成像显示突变IDH1在肿瘤中表达的潜在探针。使用锡前体以79±6％的收率（n = 9）和¹⁸的锡前体实现了AGI-5198的放射性碘化F标记是通过Ugi反应完成的，其衰变校正后的放射化学产率为2.6±1.6％（n = 5）。在酶法测定中确定了类似的非放射性化合物对突变IDH1（IDH1-R132H）的抑制能力。使用放射性标记的AGI-5198类似物进行的细胞摄取研究表明，IDH1突变的细胞的摄取比野生型IDH1细胞的摄取高。放射性标记的化合物在体内显示出良好的组织分布特征，并且在IDH1突变的肿瘤异种移植物中具有良好的初始摄取。然而，肿瘤吸收随时间减少。放射性碘标记的AGI-5198与¹⁸相比显示出更高的肿瘤与背景比F标记的AGI-5198；不幸的是，在野生型IDH1肿瘤异种移植物中也观察到了相似的结果，表明该示踪剂对突变IDH1的选择性缺乏。这些结果表明，AGI-5198类似物不是放射性示踪剂开发的有前途的平台。尽管如此，从这项研究中获得的见识可能有助于设计和优化新型化学支架，以开发用于示踪突变IDH1酶的放射性示踪剂。