Abstract View

Objectives: Gliomas are the most common central nervous system tumors in children and account for about 35% of childhood cancers. Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur early in glioma development and are associated with a much higher risk of malignant transformation. The current lack of noninvasive imaging of IDH1 and IDH2 mutations in a clinical setting is a pressing concern. Positron emission tomography (PET) is a highly sensitive, noninvasive imaging modality for studying metabolic processes, enzymes, receptors, and transporters. We hypothesize that fluorine-18-labeled vorasidenib (An FDA-approved drug in 2024), generated by substituting a fluorine-19 atom with a fluorine-18 radionuclide, could provide a real-time, quantitative, non-invasive diagnostic method for imaging IDH mutations in low-grade and diffuse gliomas.

Methods: First, the di-tert-butyloxycarbonyl (di-Boc) protected radiolabeling precursors were synthesized. 18F-radilolabeling of vorasidenib was carried out using commercially available 18F- fluoride mixed with N-protected vorasidenib (Di-Boc-vorasidenib) and its bromo analog (Br-di-Boc-vorasidenib) in the presence of additives (sodium iodide, silver(I) oxide) in anhydrous organic solvents (acetonitrile, dimethyl sulfoxide, tert-butanol) and heated to 80 ^oC to 175 ^oC. The reaction crude was analyzed by radio C18-high performance liquid chromatography (HPLC) (Chromolith® RP-18e 150x4.6mm; 0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile).

Results: We successfully synthesized di-Boc-vorasidenib and Br-di-Boc-vorasidenib as the radiolabeling precursors with over 95% purity. Radiolabeling of the di-Boc-protected vorasidenib and its bromo analog with K[18F]F at temperatures >110 ^oC revealed significant thermal instability of the radiolabeling precursors; however, the precursors were stable at 80 ^oC. The radioactivity channel revealed unreacted [18F]fluoride with a retention time between 2–4 minutes, but only a minor radioactivity peak corresponding to the product was observed at 175 ^oC with dimethyl sulfoxide as the solvent.

Conclusions: The di-Boc-protected vorasidenib and its bromo-substituted radiolabeling precursors were synthesized in good yield and with high physical stability. However, it was thermally labile during nucleophilic radiofluorination at >110 °C with minor competitive [18F]fluoride incorporation. Continuous condition optimization to increase the precursor stability and [18F]fluoride incorporation rate is ongoing in our lab.

References: [1] Zenon Konteatis, et al. Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma. ACS Med. Chem. Lett. 2020, 11, 2, 101–107.

[2] Mellinghoff IK, et al. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N. Engl. J. Med. 2023, 389, 589-601.