Influence of binding affinity and blood plasma level on cerebral pharmacokinetics and PET imaging characteristics of two novel xanthine PET radioligands for the A1 adenosine receptor

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IntroductionThe suitability of novel positron emission tomography (PET) radioligands for quantitative in vivo imaging is affected by various physicochemical and pharmacological parameters. In this study, the combined effect of binding affinity, lipophilicity, protein binding and blood plasma level on cerebral pharmacokinetics and PET imaging characteristics of three xanthine-derived A1 adenosine receptor (A1AR) radioligands was investigated in rats. MethodsA comparative evaluation of two novel cyclobutyl-substituted xanthine derivatives, 8-cyclobutyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CBX) and 3-(3-[18F]fluoropropyl)-8-(1-methylcyclobutyl)-1-propylxanthine ([18F]MCBX), with the reference A1AR radioligand 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX) was conducted. This evaluation included in vitro competition binding assays, in vitro autoradiography and in vivo PET imaging. Differences in cerebral pharmacokinetics and minimal scan duration required for quantification of cerebral distribution volume (VT) were assessed. ResultsMeasured Ki values of non-labeled CBX, MCBX and CPFPX were 10.0 ± 0.52 nM, 3.3 ± 0.30 nM and 1.4 ± 0.15 nM, respectively (n = 3–4). In vitro autoradiographic binding patterns in rat brain were comparable between the radioligands, as well as the fraction of non-specific binding (1.0–1.9%). In vivo cerebral pharmacokinetics of the novel cyclobutyl-substituted xanthines differed considerably from that of [18F]CPFPX. Brain uptake and VT of [18F]CBX were substantially lower despite the higher concentration of radiotracer in plasma. [18F]MCBX showed comparable uptake and VT, but faster cerebral kinetics than [18F]CPFPX. However, the faster kinetics of [18F]MCBX did not enable the quantification of cerebral VT in a shorter scan time. ConclusionsThe combined effect of individual physicochemical and pharmacological properties of a radiotracer on its PET imaging characteristics cannot be readily predicted. In vivo performance of the xanthine A1AR radioligands was mainly influenced by binding affinity; plasma concentrations and cerebral kinetics were of secondary importance.