Deuterium-labeled α-ketoglutarate enables metabolic imaging of the isocitrate dehydrogenase mutation in brain tumors.

Motivation: Mutations in isocitrate dehydrogenase (IDHm) define a distinct molecular class of gliomas. IDHm converts the normal metabolite α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (D-2HG), which drives tumorigenesis. Goal(s): The IDHm inhibitor vorasidenib was recently approved for treatment of IDHm glioma patients. However, non-invasive methods of imaging IDHm activity in vivo are lacking. Approach: Here, we show that deuterium metabolic imaging using diethyl-[3,3'-2H]-α-ketoglutarate allows quantification of D-2HG production and visualization of tumor burden specifically in mice bearing IDHm but not IDH wild-type gliomas. Results: Importantly, diethyl-[3,3'-2H]-α-ketoglutarate provides an early response to vorasidenib that precedes MRI-detectable volumetric alterations in mice bearing intracranial IDHm gliomas in vivo Impact: Our studies provide proof-of-concept evidence that diethyl-[3,3'-2H]-α-ketoglutarate informs on tumor burden and treatment response in IDHm gliomas. Clinical translation of diethyl-[3,3'-2H]-a-ketoglutarate will provide clinicians with a tool to monitor disease progression in IDHm glioma patients, which is currently challenging.