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Pharmacokinetic Animal PET Study of FK506 as a Potent Neuroprotective Agent

¹ Medical and Pharmacological Research Center Foundation, Ishikawa, Japan
² Advanced Technology Platform Research Laboratory, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan
³ Department of Chemical Materials Science, School of Materials Science, Japan Advanced Institute of Science and Technology, Ishikawa, Japan
⁴ Biopharmaceutical and Pharmacokinetics Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan

The immunosuppressive agent FK506 (tacrolimus) has neuroprotective properties not only in rodents but also in nonhuman primates. To improve the accuracy of clinical studies of acute stroke, clinical dose setting based on brain concentrations of agents in humans is very helpful. We have already established a rapid-synthesis method for ¹¹C-labeled FK506; therefore, in the present study, we aimed to establish a method to measure brain concentrations of FK506 using ¹¹C-FK506 PET in monkeys. Methods: Studies were performed on 3 male cynomolgus monkeys (Macaca fascicularis). FK506 (0.1 mg/kg) containing ¹¹C-FK506 was intravenously injected into the monkeys, and dynamic PET images were acquired for 30 min afterward. Arterial blood samples were collected 5 and 15 min after injection, and their radioactivities were measured by a -counter. FK506 concentrations in brain and blood were calculated in units of moles per liter using the specific activity of the injected FK506. The PET study data were validated using an enzyme-linked immunosorbent assay. Results: Seven minutes after administration, the radioactivity in the brain became constant and was maintained up to 30 min. We succeeded in measuring the FK506 concentration in the brain using ¹¹C-FK506 PET. Fifteen minutes after FK506 (0.1 mg/kg) administration, the concentrations in the cortex and striatum were 20.0 ± 1.7 ng/g and 14.1 ± 1.7 ng/g, respectively. FK506 concentrations in the blood correlated significantly with those measured by enzyme-linked immunosorbent assay. Conclusion: We successfully measured FK506 concentrations in anesthetized monkey brain and blood using ¹¹C-FK506 PET. These results indicate a potential method to measure FK506 concentrations in human brain. Additionally, a potential use for the PET technique in drug development has been demonstrated.

Key Words: FK506 • stroke • neuroprotectant • PET • brain concentration • monkey

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