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@INPROCEEDINGS{Schfer:824615,
      author       = {Schäfer, D. and Weiß, P. and Castillo Meleán, J. and
                      Zarrad, F. and Ermert, J. and Neumaier, B.},
      title        = {{P}reparation of n.c.a. 6-[18{F}]fluoro-{L}-tryptophan
                      using copper-mediated radiofluorination},
      reportid     = {FZJ-2016-07178},
      year         = {2016},
      abstract     = {Preparation of n.c.a. 6-[18F]fluoro-L-tryptophan using
                      copper-mediated radiofluorinationObjectives: The essential
                      amino acid tryptophan is involved in various physiological
                      processes. Besides protein synthesis, tryptophan is the
                      precursor for serotonin and kynurenine. An upregulated
                      utilization of tryptophan in tumor cells was reported (1).
                      The degradation product kynurenine was described as an
                      important factor in tumor growth and immune suppression (2).
                      Accordingly, labelled tryptophan could enable to trace
                      alterations of tryptophan uptake in regions of serotonergic
                      neurons (3). Until now, [18F]fluorotryptophan was labelled
                      using the Balz-Schiemann reaction (4) providing insufficient
                      radiochemical yields. A recently published isotopic exchange
                      reaction (5) appears to engender challenges in automation
                      that are preventing their routine use. In the last few
                      years, several innovative 18F-fluorination methods have been
                      published (6-8). The copper-mediated radiofluorination
                      method exhibits several major advantages like sufficient
                      RCYs, bench-stable precursors and mild reaction conditions
                      and was therefore chosen in this study. First, the synthesis
                      of an appropriate aryl boronic ester was developed. The
                      labelling step and hydrolysis were optimized with regard to
                      automation.Methods: An appropriate precursor for
                      18F-labelling was designed starting from bromo-indole. The
                      Schöllkopf’s auxiliary (9) was introduced within five
                      steps. The pinacol boronate ester was inserted using a
                      Suzuki-Miyaura coupling reaction. Figure 1: Synthesis scheme
                      for the pinacol ester tryptophan derivative 3.In preliminary
                      studies indole derivatives with the pinacol ester in
                      different position were used as model compounds. The highest
                      yields were obtained at 6-position of the indole motif.
                      Besides reaction time and temperature, different reaction
                      conditions like the type of nucleophilicity enhancer,
                      temperature, time and solvents were examined. The subsequent
                      deprotection step was optimized with regard to acid,
                      reaction time and temperature. Figure 2: Radiosynthesis of
                      6-[18F]fluoro-L-tryptophan.Results: The synthesis of the
                      appropriate precursor for copper-mediated radiofluorination
                      was achieved within six steps and an overall yield of 37
                      $\%.$ The optimized radiofluorination conditions are as
                      follows: precursor and Cu(OTf)2(py)4 were solved in
                      sulfolane/acetonitrile were given on dried
                      tetraethylammonium [18F]fluoride (TEA[18F]F) and heated for
                      20 min at 110 °C. The radiochemical conversion (RCC)
                      protected [18F]4 was 52±10 $\%$ determined by radioTLC.
                      Purification of [18F]4 from residual [18F]fluoride and
                      copper was achieved by using a silica cartridge. Highest RCC
                      for deprotection yields were obtained using 48 $\%$
                      hydrobromic acid for 25 min at 165°C giving 36.1±5 $\%$
                      RCC.The total radio synthesis of 6-[18F]fluoro-L-tryptophan
                      was carried out within 120 min including HPLC purification
                      (Figure 3) with an overall radiochemical yield of 13±4
                      $\%.$ The radiochemical purity was more than 99 $\%,$ with
                      an enantiomeric excess of 89 $\%$ and a specific activity of
                      280 GBq/µmol. Automation of the reaction as well as the
                      biological evaluation of the radiotracer is in progress.
                      Figure 3: Radioanalysis of HPLC purified
                      6-[18F]fluoro-L-tryptophan.Conclusion: The herein reported
                      method allows to obtain n.c.a. 6-[18F]fluoro- L-tryptophan
                      in high RCYs. Accordingly, the potential of this tracer
                      could be evaluated in different applications like tumor
                      detection or psychological disorders. Furthermore, an
                      automated synthesis unit equipped with a two-reactor-system
                      is in progress},
      month         = {Aug},
      date          = {2016-08-28},
      organization  = {Ninth International Conference on
                       Nuclear and Radiochemistry – NRC9,
                       Helsinki (Finnland), 28 Aug 2016 - 2
                       Sep 2016},
      subtyp        = {Plenary/Keynote},
      cin          = {INM-5},
      cid          = {I:(DE-Juel1)INM-5-20090406},
      pnm          = {573 - Neuroimaging (POF3-573)},
      pid          = {G:(DE-HGF)POF3-573},
      typ          = {PUB:(DE-HGF)6},
      url          = {https://juser.fz-juelich.de/record/824615},
}