Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 28, Issue 4, Pages 694-699Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.01.015
Keywords
IDH mutation; PET imaging; Glioma; Phenyl-glycine; IDH1 inhibitor
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Funding
- Southeastern Brain Tumor Foundation
- National Institutes of Health [CA182025]
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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 F-18-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 non-radioactive 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 F-18-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. (C) 2018 Elsevier Ltd. All rights reserved.
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