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@PHDTHESIS{Prante:44138,
      author       = {Prante, Olaf},
      title        = {{S}ynthese des $^{18}${F}-markierten {C}oenzyms
                      {U}ridindiphosphatglucose als {B}asis für die
                      $^{18}${F}-{G}lykosylierung von {G}lykoproteinen},
      volume       = {3902},
      issn         = {0944-2952},
      school       = {Univ. Köln},
      type         = {Dr. (Univ.)},
      address      = {Jülich},
      publisher    = {Forschungszentrum Jülich Gmbh Zenralbibliothek, Verlag},
      reportid     = {PreJuSER-44138, Juel-3902},
      series       = {Berichte des Forschungszentrums Jülich},
      pages        = {108 p.},
      year         = {2001},
      note         = {Record converted from VDB: 12.11.2012; Köln, Univ., Diss.
                      2001},
      abstract     = {The chemo-enzymatic radiosynthesis of no carrier added
                      (n.c.a.) uridine diphospho-2-deoxy-
                      2-[$^{18}$F]fluoro-$\alpha$-D-glucose (UDP-[$^{18}$F]FGlc)
                      was developed. In order to overcome the problem of poor
                      regioselectivity when using the commonly strategy to label
                      proteins via $^{18}$F-labelled prosthetic groups, the use of
                      enzyme systems in addition to the corresponding
                      $^{18}$F-labelled coenzymes was shown to be a reliable,
                      regioselective and mild labelling method. With regard to the
                      comparison and evaluation of the stereoselectivity of the
                      phosphorylating agents used in the chemical synthesis of
                      cold uridine diphospho-2-deoxy-2-fluoro-$\alpha$-Dglucose,
                      $^{31}$P-decoupled and $^{1}$H-NMR-studies were successfully
                      realized. Uridine diphospho-
                      2-deoxy-2-fluoro-$\alpha$-D-glucose was obtained in a 7 step
                      synthesis. Tetrabenzylpyrophosphate was shown to be a highly
                      stereoselective phosphorylating agent for FDG ($\alpha
                      /\beta$=3:1). Moreover, a multienzymatic pathway for the
                      synthesis of uridine diphospho-2-deoxy-2-fluoro-$\alpha$-
                      D-glucose was adopted starting from FDG and four
                      commercially available enzymes. This strategy was adjusted
                      to a mg-scale synthesis providing 35\% chemical yield.
                      Within the scope of this procedure, a comparison of the
                      natural substrate $\alpha$-D-glucose-1-phosphate with
                      2-fluoro-2-deoxy-$\alpha$-D-glucose-1-phosphate indicated
                      that the enzyme activity of UDP-glucose pyrophosphorylase
                      (UDP-Glc PPase) was decreased by a factor of 30. With regard
                      to the adaptability of the multiple enzyme system for the
                      radiosynthesis of n.c.a. uridine
                      diphospho-2-deoxy-2-[$^{18}$F]fluoro-$\alpha$-D-glucose a
                      rapid hexokinase-mediated phosphorylation of [$^{18}$F]FDG
                      utilizing ATP or UTP as phosphate donor was performed. A
                      further enzymatic isomerization of n.c.a
                      [$^{18}$F]FDG-6-phosphate to n.c.a.
                      [$^{18}$F]FDG-1-phosphate was limited due to the formation
                      of [$^{18}$F]FDG-1.6-diphosphate as main product.
                      Experiments using a multiple enzyme system to develop a
                      fully enzymatic synthetic route to UDP-[$^{18}$F]FGlc turned
                      out to be less efficient due to the necessity of carrier
                      added conditions. Thus, a chemo-enzymatic synthesis of
                      n.c.a. UDP-[$^{18}$8F]FGlc has been developed, starting from
                      1.3.4.6-tetra-O-acetyl-2-[$^{18}$F]fluoro-2-deoxy-D-glucose,
                      which occurs as an intermediate in the [$^{18}$F]FDG
                      synthesis. The chemical phosphorylation via MacDonald
                      reaction and subsequent deprotection led to a radiochemical
                      yield of 55\% of [$^{18}$F]FDG-1-phosphate. UDP-
                      [$^{18}$F]FGlc was synthesized enzymatically by condensation
                      of [$^{18}$F]FDG-1-phosphate with UTP in presence of UDP-Glc
                      PPase. In order to overcome the problem of decreased enzyme
                      acitivty the reaction was performed in a minimized reaction
                      volume and optimized UTP-concentration of 0.5 mmol/l leading
                      to an overall radiochemical yield of 20\% of
                      UDP-[$^{18}$F]FGlc within 110 min. The $^{18}$F-labelled
                      coenzyme UDP-[$^{18}$F]FGlc was used as a tool for
                      $^{18}$F-glycosylation of N-acetylglucosamine mediated by
                      $\beta$-1.4-galactosyltransferase. The $^{18}$F-glycosylated
                      product was obtained in a radiochemical yield of 56\% and
                      was easily isolated by solid phase extraction. In addition
                      to the general availability of [$^{18}$F]FDG worldwide, this
                      new strategy for enzymatic transfer of "activated
                      [$^{18}$F]FDG" has demonstrated its potential as a highly
                      selective and mild $^{18}$F-labelling method of glycosylated
                      biopolymers to study their pharmacokinetics using
                      positron-emission-tomography.},
      cin          = {INC},
      cid          = {I:(DE-Juel1)VDB53},
      pnm          = {Radiopharmazeutische Chemie},
      pid          = {G:(DE-Juel1)FUEK87},
      typ          = {PUB:(DE-HGF)11 / PUB:(DE-HGF)3},
      url          = {https://juser.fz-juelich.de/record/44138},
}