Imaging the Enzyme 11β-Hydroxysteroid Dehydrogenase Type 1 with PET: Evaluation of the Novel Radiotracer C-AS2471907 in Human Brain.

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme converts cortisone to cortisol and participates in the regulation of glucocorticoid levels in tissues. 11β-HSD1 is expressed in the liver, kidney, adipose tissue, placenta, and brain. 11β-HSD1 is a target for treatment of depression, anxiety, posttraumatic stress disorder, and also against age-related cognitive function and memory loss. In this study, we evaluated the radiotracer C-AS2471907 (3-(2-chlorophenyl)-4-(methyl-)-5-[2-[2,4,6-trifluorophenoxy]propan-2-yl]-4-1,2,4-triazole) to image 11β-HSD1 availability in the human brain with PET. Fifteen subjects were included in the study. All subjects underwent one 2-h scan after a bolus administration of C-AS2471907. Two subjects underwent an additional scan after blockade with the selective and high-affinity 11β-HSD1 inhibitor ASP3662 to evaluate C-AS2471907 nondisplaceable distribution volume. Five subjects also underwent an additional scan to evaluate the within-day test-retest variability of C-AS2471907 volumes of distribution (). C-AS2471907 time-activity curves were best fitted by the 2-tissue-compartment (2TC) model. C-AS2471907 exhibited a regionally varying pattern of uptake throughout the brain. The of C-AS2471907 ranged from 3.7 ± 1.5 mL/cm in the caudate nucleus to 14.5 ± 5.3 mL/cm in the occipital cortex, with intermediate values in the amygdala, white matter, cingulum, insula, frontal cortex, putamen, temporal and parietal cortices, cerebellum, and thalamus (from lowest to highest ). From the blocking scans, nondisplaceable distribution volume was determined to be 0.16 ± 0.04 mL/cm for C-AS2471907. Thus, nearly all uptake was specific and the binding potential ranged from 22 in the caudate to 90 in the occipital cortex. Test-retest variability of 2TC values was less than 10% in most large cortical regions (14% in parietal cortex) and ranged from 14% (cerebellum) to 51% (amygdala) in other regions. The intraclass correlation coefficient of 2TC values ranged from 0.55 in the white matter to 0.98 in the cerebellum. C-AS2471907 has a high fraction of specific binding in vivo in humans and reasonable within-day reproducibility of binding parameters.