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@INPROCEEDINGS{Neumaier:1027684,
      author       = {Neumaier, Bernd and Cologni, Roberta and Holschbach, Marcus
                      and Bier, Dirk and Carloni, Paolo},
      title        = {18{F}-{L}abelled inhibitors for targeting of {IDH}1 mutant
                      gliomas},
      reportid     = {FZJ-2024-04002},
      year         = {2023},
      note         = {Supported by Helmholtz European Partnership (HEP)},
      abstract     = {Objectives: Low grade diffuse gliomas are primary brain
                      tumorscharacterized by the presence of mutations in
                      isocitrate dehydrogen-ase 1 (IDH1), which equip the enzyme
                      with a neomorphic activity thatincreases production of
                      2-hydroxyglutarate [1]. High concentrations ofthis
                      oncometabolite are thought to interfere with histone
                      methylationand cellular differentiation, thereby promoting
                      gliomagenesis. Inaddition, mutated IDH1 (mIDH1) has been
                      recognized as a keybiomarker for differential diagnosis,
                      since it is not present in themore aggressive glioblastomas.
                      While current approaches for detec-tion of mIDH1 require
                      invasive tissue sampling, positron emissiontomography (PET)
                      with mIDH1-selective probes could allow for non-invasive
                      assessment of the IDH status. Here, we describe
                      thepreparation, radiofluorination and preliminary biological
                      evaluationof two candidate PET tracers derived from the
                      mIDH1-selectiveinhibitor Olutasidenib.Methods: The boronic
                      acid pinacol ester precursor for coppermediated
                      radiofluorination was prepared using para bromoaniline asthe
                      starting material and Ellman’s sulfinamide as chiral
                      auxiliary forthe formation of the desired S-enantiomer.
                      However, due to significantproduction of the undesired
                      R-enantiomer, we ultimately decided toprepare and radiolabel
                      both R- and S-enantiomer in order to comparethem in cellular
                      uptake assays. For radiofluorination, [ 18 F]fluoride
                      wasloaded onto an anion exchange cartridge and eluted with
                      TEAB inMeOH followed by removal of MeOH. An equimolar
                      solution ofradiolabeling precursor and copper mediator in
                      1,3-dimethyl-2-imidazolidinone was then added and the
                      mixture was stirred in airat 100 °C for 15 minutes,
                      followed by deprotection with 0.3 M NaOH inH2 O at 80°C for
                      3 minutes. After HPLC-purification and formulation
                      inphysiological saline solution, the radiotracers were
                      subjected to apreliminary evaluation in wildtype and
                      mIDH1-transfected U-87 MGglioma cell lines.Results: The
                      protected (S) and (R) radiolabeling precursors wereproduced
                      in 15 steps and the 18F-labeled R,S-enantiomers 2 and 3
                      werefurnished in radiochemical yields of 60 ± $11\%,$
                      radiochemical purities $of>99\%$ and molar activities of
                      102–237 GBq/μmol. Tracers lipophilicity(logD7.4 ) was
                      found to be 2.53 if measured in PBS buffer but negativewhen
                      measured in water (logP). No degradation was observed
                      duringincubation in rat blood plasma at 37°C over 60
                      minutes. In contrast ifthe tracer was spotted onto silica
                      plates full degradation was observed.Cell uptake experiments
                      revealed a significantly higher uptake intransfected rather
                      than wild type cells for both [ 18F]1 and S-[18 F]2 butwhile
                      $90\%$ of the first could reach the cytoplasm, the latter
                      mostlyremained in the medium, suggesting that it may only
                      partially cross thecellular membrane.Conclusion: Three
                      18F-labelled mIDH1-selective inhibitors havebeen
                      successfully prepared and shown to exhibit significantly
                      higheruptake into mIDH1-expressing compared to wildtype
                      glioma cells. Apreclinical evaluation will be performed on [
                      18 F]1, while furtherexperiments will be conducted on [ 18
                      F]2 to explain the unexpectedresults and subsequently
                      compare them with the results of [ 18F]3.},
      month         = {May},
      date          = {2023-05-22},
      organization  = {25th International Symposium on
                       Radiopharmaceutical Sciences, Honolulu,
                       USA (USA), 22 May 2023 - 26 May 2023},
      subtyp        = {After Call},
      cin          = {INM-5 / INM-9},
      cid          = {I:(DE-Juel1)INM-5-20090406 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {5253 - Neuroimaging (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5253},
      typ          = {PUB:(DE-HGF)6},
      url          = {https://juser.fz-juelich.de/record/1027684},
}