Profiling and occupancy study with PET imaging using a novel radioligand [¹¹C]AS2471907 for brain 11β-HSD1

Objectives 11β-HSD1 is enzyme that catalyzes the conversion of the cortisone to the active metabolite cortisol and is widely expressed through the adult CNS, and its inhibitors are expected as treating several cognitive and psychiatric disease. We have developed a PET ligand [¹¹C]AS2471907 for 11β-HSD1. The purpose of the present research is to clarify the character of the novel PET tracer, and demonstrate the usefulness to perform occupancy study for 11β-HSD1 in rodent and non-human primate brain.

Methods [¹¹C]AS2471907 was synthesized in house. Determination of the binding affinity of [¹¹C]AS2471907 by competitive binding assay was conducted with 11β-HSD1 overexpressing CHO cells in vitro using ASP3662, a selective 11β-HSD1 inhibitor. For distribution and occupancy study in rodent, [¹¹C]AS2471907 was injected via tail vein into SD rats and ddY mice, respectively. Brain region was isolated and the radioactivity was measured with a gamma counter. For PET measurements in conscious rhesus monkeys, PET scans were conducted using an animal PET scanner.

Results [¹¹C]AS2471907 showed potent affinity to 11β-HSD1, and its binding was competitively inhibited by ASP3662. For distribution studies, [¹¹C] AS2471907 had a broad distribution in the rat and monkey brain, with the highest binding in the cerebellum and cerebral cortex, respectively. Pretreatment with ASP3662 inhibited binding of [¹¹C]AS2471907 in each brain region, in a dose-dependent manner.

Conclusions [¹¹C]AS2471907 exhibited the usefulness as a PET tracer to evaluate enzyme occupancy after treatment of 11β-HSD1 inhibitor. This indicates that [¹¹C]AS2471907 is with a useful tool for both preclinical and clinical studies.