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@INPROCEEDINGS{Kolks:1027698,
      author       = {Kolks, Niklas and Zlatopolskiy, Boris and Neumaier, Bernd},
      title        = {{P}reparation of 5-[18{F}],7-difluoro- and
                      5,7-[18{F}]difluorotryptophans},
      issn         = {0969-8051},
      reportid     = {FZJ-2024-04009},
      year         = {2022},
      abstract     = {Objective: Tryptophan (Trp) is an essential proteinogenic
                      aminoacid with an indole side chain that can serve as a
                      precursor for differ-ent signaling molecules. The two main
                      branches of Trp metabolism -serotonin/melatonin biosynthesis
                      and the kynurenine pathway - aredifferentially altered in a
                      variety of neurological, psychiatric andoncological
                      diseases. Positron emission tomography (PET)
                      withradiolabeled Trp analogs like 7-[ 18 F]Fluorotryptophan
                      (7-[ 18 F]FTrp),which has been recently introduced and
                      underwent first in-humanstudies, represents a promising
                      approach for in vivo imaging of Trpmetabolism [1]. However,
                      imaging probes capable of selectivelyvisualizing different
                      Trp metabolic pathways are still lacking. Theobjective of
                      this work was the preparation of 5-[ 18 F],7-difluoro-
                      and5,7-[ 18 F]-difluorotryptophans ([ 18 F]1 and [ 18 F]2,
                      respectively). 5-FTrpis known to be a good substrate of
                      tryptophan hydroxylase (TPH), akey enzyme of
                      serotonin/melatonin biosynthesis, which transforms5-FTrp
                      into 5-HOTrp. Similarly, [ 18 F]1 should lose the 18 F-label
                      dueto 5-hydroxylation by TPH and thus enable selective
                      visualization of the kynurenine pathway. In contrast, [ 18
                      F]2 should target both mainbranches of Trp
                      metabolism.Methods: The Ni-BPB-(S,S)-5-BPin-7-F- and
                      -7-BPin-5-F-Trpprecursors (3, 4) were synthesized from
                      5-Br-7-F- and 7-Br-5-F-indoles, which were in turn prepared
                      from 4-Br-2-F- and 2-Br-4-F-anilines. Miyaura borylation of
                      these heterocylces furnished5-BPin-7-F- and
                      7-BPin-5-F-indoles, which were transformedinto
                      N,N,N-(5-Bpin-7-F-indolyl)- and
                      N,N,N-(7-Bpin-5-F-indolyl)-methyltrimethylammonium iodides
                      using a Mannich type reactionfollowed by quaternization with
                      MeI. Finally, alkylation of (S)-Ni-BPB-Gly with the
                      quaternary methylammonium salt afforded the
                      desiredradiolabeling precursors 3 and 4. The latter were 18
                      F-fluorinatedusing a modified protocol for alcohol-enhanced
                      Cu-mediated radi-ofluorination [2, 3]. Accordingly, [ 18 F]F
                      – was eluted from an anionexchange resin using Et 4 NOTf
                      in MeOH, MeOH was evaporated, and asolution of the
                      respective precursor and copper mediator in nBuOH/DMI (1:2)
                      was added. After stirring of the reaction mixture at
                      110°Cfor 10 min under air, the radiolabeled intermediates
                      Ni-BPB-(S,S)-5-[ 18 F],7-F 2 Trp ([ 18 F]5) or
                      Ni-BPB-(S,S)-5,7-[ 18 F]-F 2 Trp ([ 18 F]6) were iso-lated
                      by C 18 SPE and decomposed with 2 m HCl at 110°C for 10
                      min.Finally, HPLC purification and formulation yielded [ 18
                      F]1 and [ 18 F]2 asready-to-use solutions.Results: The
                      precursors 3 and 4 were synthesized in $13\%$ and $7\%yield$
                      over 8 steps, respectively. [ 18 F]5 and [ 18 F]6 were
                      prepared inyields of $77\%$ (non-isolated, determined by
                      HPLC). [ 18 F]1 and [ 18 F]2were produced within 68 min in
                      isolated activity yields over twosteps of $35\%$ and $33\%,$
                      respectively, and in high radiochemical andchemical
                      purities.Conclusion: 5-[ 18 F],7-difluoro- and 5,7-[ 18
                      F]-difluorotryptophanswere efficiently prepared using
                      alcohol-enhanced Cu-mediatedradiofluorination and can now be
                      subjected to biological evaluationas potential PET-probes
                      for delineation of the main Trp
                      metabolicpathways.Acknowledgements: This work was supported
                      by the GermanResearch Foundation (DFG grants ZL 65/1-1 and
                      ZL 65/3-1).References:[1] B. D. Zlatopolskiy et al.; J. Med.
                      Chem., 2018, 61, 189.[2] A. Craig et al. Chem. Commun.,
                      2020, 56, 9505-9508.[3] J. Zischler et al., Chem. Eur. J.
                      2017, 23, 3251.},
      month         = {May},
      date          = {2022-05-29},
      organization  = {24th International Symposium on
                       Radiopharmaceutical Sciences, Nantes
                       (France), 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)00110-X},
      url          = {https://juser.fz-juelich.de/record/1027698},
}