Abstract
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Objectives The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to cortisol. Inhibition of 11β-HSD1 may be a potential therapy for cognitive deficits in Alzheimer's disease and chronic pain. The aim of this study is to assess the distribution and test-retest variability of a novel PET tracer [11C]AS2471907, an 11β-HSD1 inhibitor, in the human brain.
Methods Six healthy males (33±7 y) participated, with 2 scans per day (5.1 ± 0.8 h apart). The injected dose was 122 ± 79 MBq and the injected mass was 1.26 ± 0.82 µg. A 120-min dynamic acquisition on the HRRT was performed. Time-activity curves (TACs) were generated in 11 regions of interests (ROIs) (amygdala, caudate, cerebellum, centrum semiovale, cingulate cortex, frontal cortex, insula, occipital cortex, putamen, temporal cortex, thalamus) and fitted with 1- and 2-tissue models (1T, 2T) using the arterial input function. Test-retest variability (TRV) in regional volume of distribution (VT) was assessed using average VT values weighted based on the ROI size.
Results [11C]AS2471907 metabolized slowly (90% parent fraction at 90 min post-injection). Regional brain uptake of the tracer was high, with appropriate kinetics. Highest SUV (30-90 min) was in occipital cortex (2.59±0.34), medium in frontal cortex (1.69±0.28), and lowest in white matter (0.88±0.17). TACs were well fitted with 1T model. Mean VT across five subjects (one subject excluded due to low activity dose) was 8.0±3.1 mL/cm3 (range: 3.6-12.1 mL/cm3). TRV across subjects for 1T was 11±5%, i.e., there was a mean increase in VT from morning to afternoon, which may represent a true biological effect. Conclusions: The tracer [11C]AS2471907 has good characteristics for PET imaging of 11β-HSD1 in the human brain. Previous blocking studies in nonhuman primates suggest that there is no suitable reference region for this tracer, thus arterial samples are required.