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@ARTICLE{Schneider:859684,
      author       = {Schneider, Daniela and Bier, Dirk and Bauer, Andreas and
                      Neumaier, Bernd and Holschbach, Marcus},
      title        = {{I}nfluence of incubation conditions on microsomal
                      metabolism of xanthine-derived {A}1 adenosine receptor
                      ligands},
      journal      = {Journal of pharmacological $\&$ toxicological methods},
      volume       = {95},
      issn         = {1056-8719},
      address      = {New York, NY [u.a.]},
      publisher    = {Elsevier},
      reportid     = {FZJ-2019-00523},
      pages        = {16 - 26},
      year         = {2019},
      abstract     = {Introduction:In vitro metabolism models such as liver
                      microsomes represent an important tool for the development
                      of novel radioligands.Comparability and physiological
                      relevance of invitro metabolism data criticallydepend on the
                      careful evaluation and optimization of assay protocols. We
                      therefore investigated the influence ofincubation conditions
                      on the microsomal stability of xanthine-derived A1 adenosine
                      receptor (A 1AR) ligandswhich have been developed for
                      positron emission tomography (PET).Methods:Substrate
                      depletion assays using rat liver microsomes (RLM) were
                      performed for three analogouscompounds which differ with
                      regard to the metabolically vulnerable substituent at the
                      xanthine C8 position.Incubation
                      conditionswerevariedsystematically. Additionally, the
                      stability of the cofactor NADPH duringing cubation was
                      investigated.Results:Microsomal metabolism was strongly
                      influenced by buffer pH, organic solvents and preincubation
                      time.Substrate depletion values varied up to5-fold depending
                      on incubation matrix composition, however, the rankorder of
                      metabolic stability remained unchanged. Prolonged incubation
                      periods led to drastic loss in enzymeactivity which could
                      not be prevented by addition of metal chelators or
                      antioxidants. Cofactor NADPH
                      wasrapidlyoxidizedinmicrosomalmatrix,evenintheabsenceofcytochromeP450substrates.Discussion:Insummary,short
                      incubation times, precise pH control and minimal
                      concentrations of organic solvents are mandatory to obtain
                      reliable microsomal stability data. Furthermore, invitro
                      metabolic stability of thetested A 1 AR ligands varied
                      largely depending on the particular C8 substituent.
                      Consequently, structural modifications at the xanthine C8
                      position appear to be a promising strategy for the
                      improvement of A1AR PETradioligands},
      cin          = {INM-5 / INM-2},
      ddc          = {610},
      cid          = {I:(DE-Juel1)INM-5-20090406 / I:(DE-Juel1)INM-2-20090406},
      pnm          = {573 - Neuroimaging (POF3-573)},
      pid          = {G:(DE-HGF)POF3-573},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30476620},
      UT           = {WOS:000454124000004},
      doi          = {10.1016/j.vascn.2018.11.005},
      url          = {https://juser.fz-juelich.de/record/859684},
}