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Synthesis and Evaluation of a 18F-Labeled Triazinediamine Analogue for Imaging Mutant IDH1 Expression in Gliomas by PET

  • Satish K. Chitneni*
    Satish K. Chitneni
    Department of Radiology and Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, United States
    *E-mail: [email protected]
  • Hai Yan
    Hai Yan
    Department of Pathology†, Duke University Medical Center, Durham, North Carolina 27710, United States
    More by Hai Yan
  • , and 
  • Michael R. Zalutsky
    Michael R. Zalutsky
    Department of Radiology and Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, United States
    Department of Pathology†, Duke University Medical Center, Durham, North Carolina 27710, United States
Cite this: ACS Med. Chem. Lett. 2018, 9, 7, 606–611
Publication Date (Web):May 1, 2018
https://doi.org/10.1021/acsmedchemlett.7b00478
Copyright © 2018 American Chemical Society

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    Abstract

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    Mutations in the isocitrate dehydrogenase gene 1 (IDH1) are common in gliomas. Studies suggest that IDH1 mutations are early events in glioma formation and are important drivers of malignant progression. Herein, we report the synthesis and evaluation of a 18F-labeled triazinediamine analogue, [18F]1, as a candidate radiotracer for noninvasive imaging of IDH1 mutations in gliomas by positron emission tomography (PET). In vitro studies revealed good binding inhibition potency and binding affinity for [18F]1 in IDH1 mutant glioma cell lines, with a half-maximal inhibitory concentration value (IC50) of 54 nM and an equilibrium dissociation constant (Kd) of 40 nM. In vivo studies using mutant IDH1 glioma xenografts showed good tumor uptake of [18F]1 and specific inhibition by the unlabeled 1, but also elevated radioactivity uptake in the bone, suggesting significant defluorination. The results support further optimization of the triazinediamine scaffold to develop a more stable and potent 18F-labeled analogue for PET imaging of IDH1 mutations in gliomas.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.7b00478.

    • Materials and methods for chemical syntheses, radiolabeling, in vitro and in vivo evaluation of the labeled compound, and % injected dose per gram (%ID/g) data for the biodistribution study (PDF)

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    This article is cited by 15 publications.

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