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@INPROCEEDINGS{Kreft:825290,
      author       = {Kreft, Sabrina and Bier, Dirk and Holschbach, Marcus and
                      Schulze, Annette and Coenen, Heinrich Hubert},
      title        = {{N}ew metabolically enhanced {PET} radioligands for the
                      adenosine {A}(1) receptor},
      reportid     = {FZJ-2016-07754},
      year         = {2015},
      abstract     = {Objectives
                      8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine
                      ([18F]CPFPX) is an established receptor ligand to examine
                      cerebral adenosine A1 receptors in humans by
                      positron-emission-tomography (PET) [1]. A large drawback of
                      this compound is its short biological half-life of about
                      only ten minutes in human blood plasma [2]. Therefore
                      alternative, slower metabolizing 18F-labelled adenosine A1
                      receptor ligands for in vivo imaging were developed, while
                      maintaining a high affinity. Methods The binding affinity of
                      various xanthine derivatives to the adenosine A1 receptor
                      was examined. Based on these studies as well as the results
                      of in-house studies on metabolites, the xanthine derivatives
                      8-cyclobutyl-1-cyclopropymethyl-3-(3-fluoropropyl)xanthine
                      (1) and
                      1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl)xanthine
                      (2) were designed as alternatives of CPFPX. After synthesis
                      of these compounds, their affinity to the adenosine A1
                      receptor was investigated by competitive assays. The
                      mesylate derivatives were synthesized as precursors for
                      nucleophilic 18F-labelling and the radiofluorinated ligands
                      were used for autoradiographic studies. Furthermore, the
                      metabolism of 1 and 2 was examined in vitro using human
                      liver microsomes. Results The new xanthine derivatives were
                      synthesized in 13 steps with total yields of 1.8 $\%$ (1)
                      and 1.5 $\%$ (2). In binding studies both compounds showed
                      nanomolar affinities to the adenosine A1 receptor.
                      [18F]CBCPM was obtained by radiofluorination with a
                      radiochemical yield of 21.3 ± 3.8 $\%$ and a molar activity
                      of 12.3 ± 0.2 GBq/µmol. In case of [18F]CPMMCB, a
                      radiochemical yield of 14.4 ± 2.5 $\%$ and a molar activity
                      of 36.5 ± 1.1 GBq/µmol could be achieved. In vitro
                      autoradiography with brain slices of rat showed for both
                      compounds the expected enrichment in regions known to have a
                      high adenosine A1 receptor expression, while exhibiting the
                      necessary low unspecific binding. Further studies proved a
                      significantly slower metabolism in vitro of both new
                      xanthine derivatives than CPFPX. Conclusions Two new
                      radiofluorinated affine and specific xanthine derivatives
                      were developed as possible radioligands for the adenosine A1
                      receptor with a distinct higher stability than CPFPX.
                      Acknowledgements References [1] Holschbach M. H. et al.
                      (2002) J. Med. Chem., 45, 5150-5156. [2] Bier D. et al.
                      (2006) Drug Metab. Dispos., 34, 570-576.},
      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/825290},
}