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@INPROCEEDINGS{Endepols:1027957,
      author       = {Endepols, Heike and Schneider, Daniela and Cologni, Roberta
                      and Neumaier, Felix and Bier, Dirk and Holschbach, Marcus
                      and Neumaier, Bernd},
      title        = {{D}evelopment and preclinical evaluation of
                      radiofluorinated olutasidenib derivatives for non-invasive
                      detection of mutated isocitrate dehydrogenase 1 (m{IDH}1) in
                      gliomas},
      reportid     = {FZJ-2024-04252},
      year         = {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.},
      month         = {Apr},
      date          = {2024-04-10},
      organization  = {62. Jahrestagung der Deutschen
                       Gesellschaft für Nuklearmedizin,
                       Leipzig (Germany), 10 Apr 2024 - 13 Apr
                       2024},
      subtyp        = {After Call},
      cin          = {INM-5},
      cid          = {I:(DE-Juel1)INM-5-20090406},
      pnm          = {5253 - Neuroimaging (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5253},
      typ          = {PUB:(DE-HGF)6},
      url          = {https://juser.fz-juelich.de/record/1027957},
}