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@INPROCEEDINGS{Hoffmann:910176,
      author       = {Hoffmann, Chris and Evcüman, Sibel and Neumaier, Felix and
                      Zlatopolskiy, Boris and Humpert, Swen and Bier, Dirk and
                      Holschbach, Marcus and Schulze, Annette and Endepols, Heike
                      and Neumaier, Bernd},
      title        = {[18{F}]{ALX}5406: a brain-penetrating prodrug for
                      {G}ly{T}1-specific {PET} imaging},
      issn         = {0969-8051},
      reportid     = {FZJ-2022-03656},
      year         = {2022},
      abstract     = {Objectives ALX5407 (1) is a potent and selective inhibitor
                      of glycine transporter type 1 (GlyT1) originallydeveloped
                      for the treatment of certain neurologic disorders like
                      cognitive decline or schizophrenia. While it didnot reach
                      clinical trials, ALX5407 could provide a starting point for
                      development of GlyT1-selective PET tracersand was previously
                      radiolabeled with carbon-11, but no preclinical studies have
                      been published so far. The aim ofthe present work was to
                      prepare the 18F-labeled counterpart [18F]ALX5407 ([18F]1) as
                      well as its methyl ester[18F]ALX5406 ([18F]2), and to
                      subject both candidate tracers to a preclinical
                      evaluation.Methods The radiolabeling precursor was prepared
                      by asymmetric reduction of
                      4'-bromo-3-chloropropiophenoneinto the respective
                      (R)-alcohol $(97\%$ ee), followed by etherification via
                      Mitsunobu reaction with $4-phenylphenol(>95\%$ ee),
                      amination with sarcosine methyl ester and finally Miyaura
                      borylation. The radiosynthesis wasperformed using the
                      protocol for alcohol-enhanced Cu-mediated radiofluorination.
                      To this end, a solution ofEt4NHCO3 in nBuOH (400 μL) was
                      used to elute 18F– from a QMA anion exchange cartridge
                      into a solution of theradiolabeling precursor and
                      Cu(py)4(OTf)2 (30 μmol of each) in DMA (800 μL) and the
                      reaction mixture washeated at 110 °C for 10 min under air
                      to afford [18F]2. The latter was hydrolyzed with 6 M NaOH to
                      give [18F]1.Both tracers were evaluated by in vitro
                      autoradiography in rat brain slices, in vivo μPET imaging
                      in healthy rats,and ex vivo radiometabolite analysis in rat
                      brain tissue and blood.Results The precursor was obtained in
                      $15\%$ yield over four steps. [18F]1 and [18F]2 were
                      prepared in a ready-touseform in radiochemical yields of
                      $55±7\%$ (n=8) and $62±5\%$ (n=4) within 90120 min,
                      respectively, with molaractivities of 14137 GBq/μmol. In
                      vitro evaluations showed accumulation of [18F]1 in brain
                      regions consistentwith the distribution pattern of GlyT1,
                      but in vivo brain uptake of the probe was very low. In
                      contrast, [18F]2showed no specific binding in brain slices,
                      but rapidly crossed the blood brain barrier (BBB) and showed
                      an invivo brain distribution pattern consistent with GlyT1
                      specific binding. Metabolite studies demonstrated
                      rapidhydrolysis of [18F]2 to [18F]1 in rat brain tissue and
                      blood (t1/2=12 min), confirming that it acts as a
                      BBB-penetratingprodrug.Conclusion [18F]2 is a promising and
                      readily available prodrug for preclinical PET imaging of
                      GlyT1 in the brain.Figure},
      month         = {May},
      date          = {2022-05-29},
      organization  = {24th International Symposium on
                       Radiopharmaceutical Sciences, Nantes
                       (Germany), 29 May 2022 - 3 Jun 2022},
      subtyp        = {After Call},
      cin          = {INM-5},
      ddc          = {570},
      cid          = {I:(DE-Juel1)INM-5-20090406},
      pnm          = {5253 - Neuroimaging (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5253},
      typ          = {PUB:(DE-HGF)6},
      doi          = {10.1016/S0969-8051(22)00127-5},
      url          = {https://juser.fz-juelich.de/record/910176},
}