Synthesis and evaluation of radiolabeled AGI-5198 analogues as candidate radiotracers for imaging mutant IDH1 expression in tumors.
Synthesis and evaluation of radiolabeled AGI-5198 analogues as candidate radiotracers for imaging mutant IDH1 expression in tumors.
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DOI：
10.1016/j.bmcl.2018.01.015
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发表时间：
2018-02-15
影响因子：
2.7
通讯作者：
Zalutsky MR
中科院分区：
文献类型：
--
作者：
Chitneni SK;Reitman ZJ;Spicehandler R;Gooden DM;Yan H;Zalutsky MR
代谢酶异柠檬酸脱氢酶1（IDH 1）的突变通常在神经胶质瘤中发现。AGI-5198是突变IDH 1酶的有效和选择性抑制剂，用放射性碘和氟-18进行放射性标记。这些放射性示踪剂被评估为潜在的探针，用于用正电子发射断层扫描（PET）成像肿瘤中的突变IDH 1表达。使用锡前体以79 ± 6%的产率（n=9）实现AGI-5198的放射性碘化，并且通过Ugi反应以2.6 ± 1.6%的衰变校正放射化学产率（n=5）完成18F-标记。在酶测定中测定类似非放射性化合物对突变体IDH 1（IDH 1-R132 H）的抑制效力。使用放射性标记的AGI-5198类似物的细胞摄取研究显示IDH 1突变细胞中的摄取略高于野生型IDH 1细胞。放射性标记的化合物在体内显示出有利的组织分布特征，并且在IDH 1突变的肿瘤异种移植物中具有良好的初始摄取;然而，肿瘤摄取随时间而降低。与18F标记的AGI-5198相比，放射性碘标记的AGI-5198表现出更高的肿瘤-背景比;不幸的是，在野生型IDH 1肿瘤异种移植物中也观察到类似的结果，表明该示踪剂缺乏对突变体IDH 1的选择性。这些结果表明，AGI-5198类似物不是放射性示踪剂开发的有希望的平台。尽管如此，从这项研究中获得的见解可能有助于设计和优化新型化学支架，用于开发用于成像突变IDH 1酶的放射性示踪剂。
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.
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