Schneider, Daniela (2017). Relevance of in vitro metabolism models for PET radiotracer development. PhD thesis, Universität zu Köln.


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The utility of in vitro metabolism models for the development of positron emission tomography (PET) radiotracers was evaluated using three xanthine-derived adenosine A1 receptor 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. In vivo metabolic stability and metabolite patterns of the three compounds were investigated in the rat model and compared to in vitro data generated in rat liver microsomes. Following optimisation of the microsomal assay conditions, in vitro half-lives of the test compounds were determined and expressed as ratios for the purpose of in vitro-in vivo comparison. The half-life 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 was assessed in anaesthetised rats via blood analysis. Plasma clearance values were calculated and expressed as inversed ratios to facilitate direct comparison with in vitro half-life ratios. The inversed clearance 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 and 3.1 ± 0.15. In vitro half-life ratios deviated between 19 and 71% from inversed clearance ratios. These deviations can be considered small in view of the reduced complexity of the microsomal model and the multitude of physiological parameters affecting in vivo pharmacokinetics of a substance. Visual comparison of metabolite 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 predicted by microsomal data. This result encourages the implementation of in vitro metabolism studies as an integral part of PET radiotracer development.

Item Type: Thesis (PhD thesis)
CreatorsEmailORCIDORCID Put Code
Schneider, Danielad.schneider@fz-juelich.deUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-76950
Date: May 2017
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Ehemalige Fakultäten, Institute, Seminare > Faculty of Mathematics and Natural Sciences > Institute of Nuclear Chemistry
Subjects: Chemistry and allied sciences
Medical sciences Medicine
Uncontrolled Keywords:
radiotracer; positron emission tomography; in vitro metabolism models; liver microsomes; A1 adenosine receptor; CPFPXEnglish
Date of oral exam: 5 July 2017
NameAcademic Title
Ermert, JohannesProf. Dr.
Baumann, UlrichProf. Dr.
Refereed: Yes


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