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@INPROCEEDINGS{Hoffmann:1026486,
      author       = {Hoffmann, Chris and Kolks, Niklas and Gröner, Benedikt and
                      Urusova, Elizaveta and Endepols, Heike and Neumaier, Felix
                      and Neumaier, Bernd and Zlatopolskiy, Boris},
      title        = {{N}ext generation copper complexes for efficient production
                      of radiolabeled aromatics},
      reportid     = {FZJ-2024-03430},
      year         = {2023},
      abstract     = {Objectives: Cu-mediated radiofluorination is a versatile
                      tool for thepreparation of radiofluorinated
                      (hetero)aromatics from readily accessibleboronate (-B(OH)2,
                      -Bpin) or trialkylstannyl (-SnR3) substrates. Themain
                      drawback of this procedure is a requirement for large
                      amounts ofprecursor and mediator (≥20 μmol) to achieve
                      reproducibly highradiochemical conversions (RCCs), which
                      often complicates purification.The aim of this work was the
                      preparation of a series of copper(II)complexes and the
                      statistical evaluation of their suitability asmediators for
                      radiofluorination. In addition, reaction parameters(reaction
                      solvent, temperature and time) were optimized, and
                      thepractical applicability of the modified protocol was
                      confirmed byproduction of several well-known PET
                      tracers.Methods: [18F]Fluoride was loaded onto a QMA-CO3
                      cartridge andeluted with Et4NOTf (1 mg) in nBuOH (400 μL)
                      directly into a solutionof the respective boronate precursor
                      (≤10 μmol) and Cu-complex(10 μmol) in DMA, PC, or DMI
                      (800 μL). For stannyl substrates, [18F]F−elution was
                      performed with Et4NOTf (1 mg) in MeOH (500 μL)followed by
                      removal of MeOH and addition of a solution of therespective
                      stannyl precursor (≤10 μmol) and Cu-complex (10
                      μmol).The reaction mixtures were heated at 110 °C for 10
                      min and RCCs weredetermined by radio-HPLC. 4-Ph- and
                      4-Ac-Ph-X [X = B(OH)2, Bpin,Bneo, and SnMe3] were used as
                      model substrates. The results of thescreening experiments
                      were statistically evaluated using GraphPadPrism software.
                      For further optimization, reactions were performed
                      atdifferent temperatures (60–150 °C) and reaction times
                      (1–40 min). Theoptimized conditions were used for manual
                      or automated (AllinOne,Trasis) synthesis of seven known PET
                      tracers (precursor amount:≤10 μmol).Results: Out of a
                      total of 36 evaluated Cu-complexes, especially theuse of
                      Cu(4-PhPy)4(ClO4)2 and Cu(3,4-Me2Py)4(OTf)2 in nBuOH/DMI
                      orDMI resulted in considerably improved RCCs in relation to
                      previousprotocols $[≥57\%$ for Ar-B(OH)2/BPin/Bneo;
                      $≥47\%$ for Ar-SnMe3;previous protocols: $2–30\%].$
                      Additionally, with Cu(4-PhPy)4(ClO4)2,high and reproducible
                      RCCs of up to $84\%$ were obtained over a broadtemperature
                      range (80–130 °C) and reaction times (5–20 min).
                      Atreaction temperatures below 80 °C, radiofluorination of
                      the respectiveboronic acid precursor afforded 4-[18F]F-Ph-Ph
                      in good RCCs of $69–80\%when$ the reaction time was
                      increased to 40 min. Application of the optimized reaction
                      conditions for the preparation of the PET
                      tracers[18F]R91150, [18F]ALX5407 and (S)-/(R)-3-[18F]FPhes
                      afforded isolatedactivity yields (AYs) of $23–41\%$ (Lit.:
                      $10–17\%).$ RCCs of up to $75\%$ for thepreparation of
                      (S)-3-[18F]FPhe and 6-[18F]FDOPA were obtained withprecursor
                      amounts as lowas 2.5 μmol, which resulted in AYs of
                      $23–30\%after$ deprotection of the respective radiolabeled
                      intermediates andHPLC isolation. Production of
                      (S)-3-[18F]FPhe in an automatedsynthesis module using 2.5
                      μmol precursor afforded the desired PETprobein AYs of 18 ±
                      $3\%.Conclusions:$ Our screening study led to the discovery
                      of severalhighly efficient mediators for Cu-mediated
                      radiofluorination, which,especially, in nBuOH/DMI or DMI,
                      enabled highly efficient 18F-labelingof different boronic
                      and stannyl substrates. The practicality of themethod was
                      demonstrated by preparation of several
                      radiotracers,including 6-[18F]FDOPA, in improved
                      radiochemical yields and/orusing significantly lower
                      precursor loadings.},
      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},
      cid          = {I:(DE-Juel1)INM-5-20090406},
      pnm          = {5253 - Neuroimaging (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5253},
      typ          = {PUB:(DE-HGF)6},
      url          = {https://juser.fz-juelich.de/record/1026486},
}