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| Hauptseite > Publikationsdatenbank > Development and preclinical evaluation of radiofluorinated olutasidenib derivatives for non-invasive detection of mutated isocitrate dehydrogenase 1 (mIDH1) in gliomas |
| Hauptseite > Publikationsdatenbank > Development and preclinical evaluation of radiofluorinated olutasidenib derivatives for non-invasive detection of mutated isocitrate dehydrogenase 1 (mIDH1) in gliomas |
| Conference Presentation (After Call) | FZJ-2024-04252 |
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2024
Abstract: Ziel/Aim: Mutations of isocitrate dehydrogenase 1 (IDH1) are key biomarkers for glioma classification, but current methods for detection of mutated IDH1 (mIDH1) require invasive tissue sampling. The aim of the present work was to develop radiofluorinated analogs of the mIDH1-selective inhibitor olutasidenib as positron emission tomography (PET) probes for non-invasive detection of mIDH1.Methodik/Methods: Four radiolabeled olutasidenib derivatives were prepared by Cu-mediated radiofluorination of suitable boronic acid pinacol esters or aliphatic radiofluorination under ‘minimalist’ conditions. They were characterized by cellular uptake studies, using U87 glioma cells with a heterozygous IDH1R132H mutation (U87-mIDH1) and the corresponding wildtype cells (U87-WT). In addition, PET imaging in mice with subcutaneous U87-mIDH1 and U87-WT tumors was used to evaluate the in vivo biodistribution and mIDH1-selectivity of the most promising probe. Apart from analyzing semiquantitative SUV, kinetic modeling was performed using PMOD.Ergebnisse/Results: All four probes effectively inhibited mIDH1, with [F-18]mIDH-138 displaying the highest potency (IC50=103 nM). [F-18]mIDH-138 also showed significantly higher cellular accumulation in U87-mIDH1 compared to U87-WT cells, while none of the other probes exhibited preferential in vitro uptake into U87-mIDH1 cells. PET imaging demonstrated a good in vivo stability and low non-specific uptake of [F-18]mIDH-138, but also revealed significantly higher uptake into U87-WT compared to U87-mIDH1 tumors. This was confirmed by kinetic modeling, which showed significantly higher total and specific distribution volumes as well as binding potentials (BPND) in U87-WT tumors.Schlussfolgerungen/Conclusions: In conclusion, the results indicate that mIDH1-selective inhibition may not directly correlate with mIDH1-selective target engagement and that in vivo engagement of wildtype and mutated IDH1 may be governed by factors that are not faithfully reproduced by in vitro assays, both of which could complicate development of PET probes.
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