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@ARTICLE{Cologni:1030251,
      author       = {Cologni, Roberta and Holschbach, Marcus and Schneider,
                      Daniela and Bier, Dirk and Schulze, Annette and Stegmayr,
                      Carina and Endepols, Heike and Ermert, Johannes and
                      Neumaier, Felix and Neumaier, Bernd},
      title        = {{P}reparation and {P}reclinical {E}valuation of
                      18{F}-{L}abeled {O}lutasidenib {D}erivatives for
                      {N}on-{I}nvasive {D}etection of {M}utated {I}socitrate
                      {D}ehydrogenase 1 (m{IDH}1)},
      journal      = {Molecules},
      volume       = {29},
      number       = {16},
      issn         = {1420-3049},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {FZJ-2024-05268},
      pages        = {3939},
      year         = {2024},
      note         = {This research was funded by Deutsche Forschungsgemeinschaft
                      (DFG), grant number NE 890/9-1, and by the Helmholtz
                      European Partnering program (‘Innovative high-performance
                      computing approaches for molecular neuromedicine’).},
      abstract     = {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 and cannot be used for longitudinal studies.
                      Positron emission tomography (PET) imaging with
                      mIDH1-selective radioligands is a promising alternative
                      approach that could enable non-invasive assessment of the
                      IDH status. In the present work, we developed efficient
                      protocols for the preparation of four 18F-labeled
                      derivatives of the mIDH1-selective inhibitor olutasidenib.
                      All four probes were characterized by cellular uptake
                      studies with U87 glioma cells harboring a heterozygous IDH1
                      mutation (U87-mIDH) and the corresponding wildtype cells
                      (U87-WT). In addition, the most promising probe was
                      evaluated by PET imaging in healthy mice and mice bearing
                      subcutaneous U87-mIDH and U87-WT tumors. Although all four
                      probes inhibited mIDH1 with variable potencies, only one of
                      them ([18F]mIDH-138) showed significantly higher in vitro
                      uptake into U87-mIDH compared to U87-WT cells. In addition,
                      PET imaging with [18F]mIDH-138 in mice demonstrated good in
                      vivo stability and low non-specific uptake of the probe, but
                      also revealed significantly higher uptake into U87-WT
                      compared to U87-mIDH tumors. Finally, application of a
                      two-tissue compartment model (2TCM) to the PET data
                      indicated that preferential tracer uptake into U87-WT tumors
                      results from higher specific binding rather than from
                      differences in tracer perfusion. In conclusion, these
                      results corroborate recent findings that mIDH1-selective
                      inhibition may not directly correlate with mIDH1-selective
                      target engagement and indicate 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.},
      cin          = {INM-5},
      ddc          = {540},
      cid          = {I:(DE-Juel1)INM-5-20090406},
      pnm          = {5253 - Neuroimaging (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5253},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {39203017},
      UT           = {WOS:001306947000001},
      doi          = {10.3390/molecules29163939},
      url          = {https://juser.fz-juelich.de/record/1030251},
}