Synthesis of [1-C-13-5-C-12]-alpha-ketoglutarate enables noninvasive detection of 2-hydroxyglutarate

• Type of Material: Article
• Authors: Natsuko Miura, National Cancer Institute, NIH, Bethesda; Chandrasekhar Mushti, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda; Deepak Sail, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda; Jenna E AbuSalim, National Cancer Institute, NIH, Bethesda; Kazutoshi Yamamoto, National Cancer Institute, NIH, Bethesda; Jeffrey R Brender, National Cancer Institute, NIH, Bethesda; Tomohiro Seki, National Cancer Institute, NIH, Bethesda; Deyaa AbuSalim, Indiana University; Shingo Matsumoto, National Cancer Institute, NIH, Bethesda; Kevin A Camphausen, National Cancer Institute, NIH, Bethesda; Murali C Krishna, National Cancer Institute, NIH, Bethesda; Rolf E Swenson, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda; Aparna Kesarwala, Emory University
• Language: English
• Date: 2021-07-14
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
• Final Published Version (URL): http://dx.doi.org/10.1002/nbm.4588
• Title of Journal or Parent Work: NMR IN BIOMEDICINE
• Volume: 34
• Issue: 11
• Start Page: e4588
• End Page: e4588
• Keywords: ISOCITRATE DEHYDROGENASE 1; ONCOMETABOLITE 2-HYDROXYGLUTARATE; IDH2 MUTATIONS; carbon-13 labeled metabolites; hyperpolarized carbon-13 nuclear magnetic resonance spectroscopy; 2-hydroxyglutarate; Biophysics; Radiology, Nuclear Medicine & Medical Imaging; alpha-ketoglutarate; Life Sciences & Biomedicine; MRS; Spectroscopy; GLIOMA-CELLS; QUANTIFICATION; isocitrate dehydrogenase 1; ACCURACY; BIOMARKER; 3 T; Technology; Science & Technology

Abstract

Isocitrate dehydrogenase 1 (IDH1) mutations that generate the oncometabolite 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG) have been identified in many types of tumors and are an important prognostic factor in gliomas. 2-HG production can be determined by hyperpolarized carbon-13 magnetic resonance spectroscopy (HP-13C-MRS) using [1-13C]-α-KG as a probe, but peak contamination from naturally occurring [5-13C]-α-KG overlaps with the [1-13C]-2-HG peak. Via a newly developed oxidative-Stetter reaction, [1-13C-5-12C]-α-KG was synthesized. α-KG metabolism was measured via HP-13C-MRS using [1-13C-5-12C]-α-KG as a probe. [1-13C-5-12C]-α-KG was synthesized in high yields, and successfully eliminated the signal from C5 of α-KG in the HP-13C-MRS spectra. In HCT116 IDH1 R132H cells, [1-13C-5-12C]-α-KG allowed for unimpeded detection of [1-13C]-2-HG. 12C-enrichment represents a novel method to circumvent spectral overlap, and [1-13C-5-12C]-α-KG shows promise as a probe to study IDH1 mutant tumors and α-KG metabolism.