Discovery of a novel radioligand [¹¹C] AS2471907 for PET imaging of the brain 11β-HSD1

Objectives 11β-HSD1 is enzyme that converts inactive cortisone to active cortisol and is widely expressed through the adult CNS. The elevation of 11β-HSD1 in brain is observed with aging and it is considered as one of causes of cognitive decline, therefore, the 11β-HSD1 inhibitor is expected to prevent cognitive defects with aging. The purpose of the present research is to develop a novel PET tracer for 11β-HSD1, which is useful for the evaluation of enzyme occupancy by treatment of 11β-HSD1 inhibitors.

Methods A number of novel 11β-HSD1 inhibitors were designed and synthesized, and five compounds were selected as candidates of PET tracer based on the assay for enzyme inhibition to 11β-HSD1 in vitro. Radiolabeling was performed in one step using ¹¹C-CH₃OTf, and PET measurements were carried out in conscious rhesus monkeys using an animal PET scanner under baseline and blocking conditions.

Results Five radiolabeled compounds were synthesized successfully with >95% radiochemical purity, and evaluated biodistribution of each radioligand in monkey brain. All tracers exhibited high brain penetration and the time activity curves of brain showed rapid uptake (>2 SUV) for the first 5 min. Two tracers, AS2471907 and its analogue possess good specific binding signal in the brain compared with other tracers, and pretreatment with a selective and high affinity 11β-HSD1 inhibitor ASP3662 (0.01-1 mg/kg, iv) markedly reduced the [¹¹C] AS2471907 uptake in 11β-HSD1 rich regions. We identified [¹¹C] AS2471907 as a novel PET tracer for 11β-HSD1, with high affinity, selectivity, and favorable property in brain.

Conclusions [¹¹C]AS2471907 possesses desirable properties as a PET tracer to evaluate enzyme occupancy after treatment of a potent and selective 11β-HSD1 inhibitor. This indicates that [¹¹C]AS2471907 is a useful tool for both preclinical and clinical studies.