Proof That Mouse and Human Metabolism and Biodistribution Is Similar

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To apply the information obtained in the knockout mice to humans, mouse and human metabolism were compared using hepatocytes [54]. To this end, the metabolic profile of FP-TZTP was studied in rat and human hepatocytes using liquid chromatography and mass spectrometry and, when possible, compared with independently synthesised standards. In both human and rat hepatocytes, the major metabolite results from oxidation of the nitrogen in the 1-methyltetrahydropy-ridine ring. Other metabolites result from sulfur oxidation, demethylation of the tertiary amine and oxidation of the tetrahydropyridine ring. The metabolism of FP-TZTP in vivo in rats is similar to that obtained in rat hepatocytes. From our knowledge of the structure of the metabolites, we have developed a two-step extraction sequence that allows the isolation of unmetab-olized parent compound. This method allows rapid determination of the parent fraction in plasma and does not require time-consuming chromatographic analysis.

Isolation Mice Hepatocytes

Figure 17.7. Regional brain localisation of [18F]-FP-TZTP in M2 knockout compared to wild-type mice at 30 minutes post-injection (sagittal slice ~1.8 mm from the midline). In the knockout mice, note the decrease in radioactivity an all grey matter regions with a high percentage of M2 receptors including cerebellum (CB), brain stem (BS) and thalamus (TH).

Figure 17.7. Regional brain localisation of [18F]-FP-TZTP in M2 knockout compared to wild-type mice at 30 minutes post-injection (sagittal slice ~1.8 mm from the midline). In the knockout mice, note the decrease in radioactivity an all grey matter regions with a high percentage of M2 receptors including cerebellum (CB), brain stem (BS) and thalamus (TH).

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