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@ARTICLE{Schneider:891082,
      author       = {Schneider, Daniela and Bier, Dirk and Holschbach, Marcus
                      and Bauer, Andreas and Neumaier, Bernd},
      title        = {{S}pecies {D}ifferences in {M}icrosomal {M}etabolism of
                      {X}anthine-{D}erived {A}1 {A}denosine {R}eceptor {L}igands},
      journal      = {Pharmaceuticals},
      volume       = {14},
      number       = {3},
      issn         = {1424-8247},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {FZJ-2021-01353},
      pages        = {277 -},
      year         = {2021},
      abstract     = {Tracer development for positron emission tomography (PET)
                      requires thorough evaluation of pharmacokinetics,
                      metabolism, and dosimetry of candidate radioligands in
                      preclinical animal studies. Since variations in
                      pharmacokinetics and metabolism of a compound occur in
                      different species, careful selection of a suitable model
                      species is mandatory to obtain valid data. This study
                      focuses on species differences in the in vitro metabolism of
                      three xanthine-derived ligands for the A1 adenosine receptor
                      (A1AR), which, in their 18F-labeled form, can be used to
                      image A1AR via PET. In vitro intrinsic clearance and
                      metabolite profiles of
                      8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX),
                      an established A1AR-ligand, and two novel analogs,
                      8-cyclobutyl-3-(3-fluoropropyl)-1-propylxanthine (CBX) and
                      3-(3-fluoropropyl)-8-(1-methylcyclobutyl)-1-propylxanthine
                      (MCBX), were determined in liver microsomes from humans and
                      preclinical animal species. Molecular mechanisms leading to
                      significant differences between human and animal metabolite
                      profiles were also examined. The results revealed
                      significant species differences regarding qualitative and
                      quantitative aspects of microsomal metabolism. None of the
                      tested animal species fully matched human microsomal
                      metabolism of the three A1AR ligands. In conclusion,
                      preclinical evaluation of xanthine-derived A1AR ligands
                      should employ at least two animal species, preferably rodent
                      and dog, to predict in vivo behavior in humans.
                      Surprisingly, rhesus macaques appear unsuitable due to large
                      differences in metabolic activity towards the test
                      compounds.},
      cin          = {INM-5 / INM-2},
      ddc          = {610},
      cid          = {I:(DE-Juel1)INM-5-20090406 / I:(DE-Juel1)INM-2-20090406},
      pnm          = {525 - Decoding Brain Organization and Dysfunction
                      (POF4-525)},
      pid          = {G:(DE-HGF)POF4-525},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {33803861},
      UT           = {WOS:000634083300001},
      doi          = {10.3390/ph14030277},
      url          = {https://juser.fz-juelich.de/record/891082},
}