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@PHDTHESIS{Schneider:836190,
      author       = {Schneider, Daniela},
      title        = {{R}elevance of in vitro metabolism models for {PET}
                      radiotracer development},
      school       = {Universität zu Köln},
      type         = {Dr.},
      reportid     = {FZJ-2017-05313},
      pages        = {140},
      year         = {2017},
      note         = {Universität zu Köln, Diss., 2017},
      abstract     = {The application of positron emission tomography (PET) as a
                      tool for molecular imaging of the brain islimited by the
                      availability of suitable radiotracers. In radiotracer
                      development, success or failure of anovel compound is
                      determined by numerous physicochemical and pharmacological
                      factors of whichmetabolism represents a particularly
                      important one. Hence, an initial assessment of the
                      metabolicproperties of a candidate radiotracer at an early
                      stage of the development process prior to expensiveand
                      time-consuming animal studies is desirable. Various in vitro
                      metabolism models are available forthe evaluation of
                      candidate drugs in the pharmaceutical sector, however, since
                      drug and tracerapplications differ fundamentally (especially
                      with regard to the amount of administered substance)
                      thequestion rises whether these models are also capable of
                      providing relevant and valid data for theevaluation of
                      radiotracers. In the present work, this question was
                      examined using three xanthinederivedadenosine A1 receptor
                      (A1AR) ligands,
                      8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine(CPFPX),
                      8-cyclobutyl-3-(3-fluoropropyl)-1-propylxanthine (CBX) and
                      3-(3-fluoropropyl)-8-(1-methylcyclobutyl)-1-propylxanthine
                      (MCBX) as model compounds. Radioligands for imaging
                      adenosinereceptors in vivo are of particular interest for
                      biomedical research since this receptor system has
                      beenassociated with numerous physiological functions (e.g.
                      regulation of sleep) and pathophysiologicalconditions (e.g.
                      Alzheimer’s and Parkinson’s disease). In vivo metabolic
                      stability and metabolitepatterns of the three A1AR ligands
                      were investigated in the rat model and compared to in vitro
                      datagenerated in rat liver microsomes. Prior to the
                      characterisation of the microsomal metabolism of thetest
                      compounds, the influence of incubation conditions on the in
                      vitro test results was assessed and themicrosomal assay was
                      optimised in order to provide physiologically relevant data.
                      Metabolic activity inliver microsomes was strongly
                      influenced by the pH value of the buffer medium and the type
                      andconcentration of the organic solvent used to solubilise
                      the test compounds. Variations of incubationmatrix
                      composition resulted in variations of individual substrate
                      depletion values of up to $500\%,whereas$ substrate
                      depletion ratios proved to be highly constant. In vitro
                      microsomal half-lives (t1/2) ofthe compounds were determined
                      and expressed as ratios for the purpose of later in vitro-in
                      vivocomparison. The t1/2 ratios (± SE) of CBX:CPFPX,
                      MCBX:CPFPX and CBX:MCBX were 3.1 ± 0.11,1.4 ± 0.029 and
                      2.2 ± 0.033. In vivo metabolic stability of the
                      18F-labelled compounds were assessed inanaesthetised rats
                      via blood analysis. Plasma clearance (CL) values were
                      calculated and expressed asinversed ratios to facilitate
                      direct comparison with in vitro t1/2 ratios. The inversed CL
                      ratios (± SE) of[18F]CBX:[18F]CPFPX, [18F]MCBX:[18F]CPFPX
                      and [18F]CBX:[18F]MCBX were 2.6 ± 0.12, 0.82 ± 0.019
                      and3.1 ± 0.15. In vitro t1/2 ratios deviated between 19 and
                      $71\%$ from inverse CL ratios. These deviationscan be
                      considered small in view of the reduced complexity of the
                      microsomal model and the multitudeof physiological
                      parameters affecting in vivo pharmacokinetics of a
                      substance. Visual comparison ofmetabolite profiles generated
                      in vitro and in vivo revealed a high degree of similarity.
                      In conclusion,both quantitative and qualitative aspects of
                      radiotracer metabolism could be reasonably well predictedby
                      microsomal data. This result encourages the implementation
                      of in vitro metabolism studies as anintegral part of PET
                      radiotracer development.},
      cin          = {INM-2},
      cid          = {I:(DE-Juel1)INM-2-20090406},
      pnm          = {571 - Connectivity and Activity (POF3-571)},
      pid          = {G:(DE-HGF)POF3-571},
      typ          = {PUB:(DE-HGF)11},
      url          = {https://juser.fz-juelich.de/record/836190},
}