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@INPROCEEDINGS{Drerup:825272,
      author       = {Drerup, Christian and Brandt, Marie and Ermert, Johannes
                      and Coenen, Heinrich Hubert},
      title        = {{S}ynthesis of an {F}-18-labelled {NO}-synthase inhibitor},
      reportid     = {FZJ-2016-07743},
      year         = {2015},
      abstract     = {Objectives: Nitric oxide (NO), an important signalling
                      molecule in the human body, is synthesised by three isoforms
                      of NO-synthase (NOS) from the amino acid L-arginine.
                      Overproduction of NO by neuronal NOS has been associated
                      with neurodegenerative disorders. Therefore, developing
                      small molecules for selective inhibition of nNOS over
                      related isoforms (iNOS and eNOS) is therapeutically
                      desirable and of great interest for decoding
                      neurodestructive key factors [1]. Suitable 18F-labelled
                      NOS-Inhibitors should allow the investigation of
                      NOS-function by molecular imaging. Potentially, the highly
                      selective nNOS Inhibitor
                      6-((3-((3-fluorophenylethylamino)methyl)phenoxy)methyl)-4-methyl-pyridine-2-amine
                      [2] is a suitable target for labelling with n.c.a.
                      [18F]fluoride in addition to the established iNOS inhibitor
                      6-(2-[18F]fluoropropyl)-4-methylpyridine-2-amine
                      [3].Methods: Based on
                      tert-butyl-(3-iodophenylethyl)carbamate the corresponding
                      iodoniumylide precursor was formed [4]. The activated
                      aromatic system was labelled with n.c.a. [18F]fluoride and
                      converted via reductive amination followed by microwave
                      assisted displacement of the protecting groups to the
                      desired nNOS inhibitor. For the development of a simplified
                      late-stage labelling procedure the corresponding brominated,
                      Boc- and pyrrole-protected compound was synthesised, which
                      was converted via borylation into the boronic ester
                      precursor. This compound was labelled authentically by
                      copper(II) mediated n.c.a. 18F-fluorination [5]. Further
                      developments enabled the one-pot synthesis by adapting the
                      [18F]fluoride activation to the radiolabelling step leading
                      to ready-to-automate conditions. Furthermore, an automated
                      one-pot procedure for the synthesis of the iNOS-Inhibitor
                      was examined after stability tests and kinetic
                      studies.Results: The n.c.a. 18F-fluorination of the
                      iodoniumylide precursor proceeded efficiently and
                      regioselective in 79 $\%$ radiochemical yield (RCY). The
                      following built-up synthesis led to the desired nNOS
                      inhibitor in 15 $\%$ RCY. First attempts of the late-stage
                      copper(II) mediated n.c.a. 18F-fluorination led to similar
                      conversions. The labelling procedure was reduced to a
                      simplified one-pot synthesis. Conclusion: Finally, there are
                      now potential and isoform selective radiotracers for both
                      inducible and neuronal NO-synthases with high molar
                      activities for further evaluations and preclinical
                      studies.References: [1] Mukherjee P. et al. (2014), Chem.
                      Soc. Rev., 43, 6814-6838.[2] Jing Q. et al. (2013), Bioorg.
                      Med. Chem., 21, 5323. [3] Zhou D. et al. (2009), J. Med.
                      Chem., 52, 2443.[4] Cardinale J. et al. (2013), Tetr. Lett.,
                      54, 2067.[5] Tredwell M. et al. (2014), Angew. Chem. Int.
                      Ed., 53, 7751.},
      month         = {May},
      date          = {2015-05-26},
      organization  = {21st International Symposium on
                       Radiopharmaceutical Sciences, Columbia
                       (USA), 26 May 2015 - 31 May 2015},
      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/825272},
}