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@INPROCEEDINGS{Holschbach:1027692,
      author       = {Holschbach, Marcus and Humpert, Swen and Schneider, Daniela
                      and Schulze, Annette and Bier, Dirk and Neumaier, Bernd},
      title        = {8-{B}icycloalkyl-{CPFPX} derivatives as potent and
                      selective tools for {PET} imaging of the {A}1 adenosine
                      receptor},
      issn         = {0969-8051},
      reportid     = {FZJ-2024-04004},
      year         = {2022},
      abstract     = {Objectives: The first successful in-house development [1]
                      ofa radiofluorinated A 1 adenosine receptor (A1AR)
                      antagonist withnanomolar affinity for the bovine A 1 AR for
                      in vivo PET studies was8-cyclopentyl-3-(3-[ 18
                      F]Fluoropropyl)-1-propyl-xanthine, [ 18 F]CPFPX. Although
                      this ligand proved to be useful in vivo in rodents,already
                      first preclinical studies revealed possible limitations for
                      PETimaging. At the beginning our efforts aimed at
                      synthesizing metabol-ically stabilized CPFPX derivatives,
                      but the recently published findingby Schneider et al. [2]
                      that affinity is the key pharmacokinetic deter-minant of
                      radiolabeled xanthines in the brain prompted us to focusour
                      efforts on the synthesis of A1AR ligands with high
                      affinity.Methods: In search of CPFPX-like A1AR ligands with
                      higher targetaffinity, we decided to replace the cyclopentyl
                      residue in the 8-posi-tion of the xanthine backbone with
                      sterically more demanding nor-bornyl residues [3]. The
                      target xanthines and the radiofluorinationprecursors
                      (sulfonates) were synthesized through multistep syn-theses
                      by a modified Traube protocol [4]. Binding experiments
                      wereperformed with membranes from CHO K1 cells stably
                      transfectedwith either the human A1 or A2AAR. Nucleophilic
                      radiofluorinationon the n.c.a level used the classical
                      Kryptofix™ 2.2.2/K 2 CO 3 method.For in vitro
                      autoradiography, frozen horizontal sections (20 μm) of
                      ratbrains were used.Results: From a series of newly
                      synthesized compounds 1-NBXhas emerged as the most potent
                      and selective candidate (Figure 1).The norbornyl group has
                      two surfaces, one being essentially a cyclo-pentyl ring
                      backed by a two-carbon bridge and the other being
                      acyclohexyl ring backed by a one-carbon bridge. The greater
                      potencyof 1-NBX relative to the 2- and 7-norbornyl isomers
                      probably occursbecause 1-NBX binds to the receptor with its
                      cyclopentyl surfacefacing the receptor, whereas the 2- and
                      7-isomers are forced to bindwith the less favorable
                      cyclohexyl ring facing the receptor.Cyclopentane exists
                      mainly in an “envelope” conformation, in whichfour of
                      the carbons form the corners of a flat envelope, and the
                      fifthcarbon represents the apex of a triangular flap, which
                      projects at anangle of about 120° from the body of the
                      envelope [5, 6]. Althoughany of the carbons can take the
                      out-of-plane position in cyclopen-tane, in norbornane the
                      bridging carbon is locked in this position.The greater
                      affinity of 1-NBX compared to that of CPFPX is mostlikely
                      due to the former being locked in the optimal conformation.
                      Asexpected from earlier studies, 1-propyl and
                      3-fluoropropylsubstitution at both 1- and 3-positions of the
                      xanthine scaffold wasoptimum to potent and selective A1AR
                      antagonism.#Conclusions: [ 18 F]1-NBX seems to be a
                      promising A1AR antagonisttracer suitable for PET. Future
                      preclinical studies will reveal weather1 NBX will have the
                      potential to serve as a substitute for [ 18
                      F]CPFPX.References:[1] Holschbach et al., J Med Chem. 2002,
                      45(23), 5150-5156.[2] Schneider et al., Nucl Med Biol. 2020,
                      82-83, 1-8.[3] Shimada et al., J Med Chem. 1992, 35,
                      924-930.[4] Holschbach et al., Org Lett. 2009, 11,
                      4266-4269.[5] Dragojlovic V., ChemTexts 2015, 1, 14.[6]
                      Trivedi et al., J Med Chem 1989, 32, 8-11},
      month         = {May},
      date          = {2022-05-29},
      organization  = {24th International Symposium on
                       Radiopharmaceutical Sciences, Nantes
                       (France), 29 May 2022 - 3 Jun 2022},
      subtyp        = {After Call},
      cin          = {INM-5},
      ddc          = {570},
      cid          = {I:(DE-Juel1)INM-5-20090406},
      pnm          = {5253 - Neuroimaging (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5253},
      typ          = {PUB:(DE-HGF)6},
      doi          = {10.1016/S0969-8051(22)00096-8},
      url          = {https://juser.fz-juelich.de/record/1027692},
}