IMAGING THE ENZYME 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 WITH POSITRON EMISSION TOMOGRAPHY: EVALUATION OF THE NOVEL RADIOTRACER 11 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, placenta and brain. 11β-HSD1 is a target for treatment of depression, anxiety, PTSD and also against age-related cognitive function and memory loss. In this study, we evaluated the radiotracer 11 C-AS2471907 (3-(2-chlorophenyl)-4-(methyl-11 C )-5-[2-[2,4,6-trifluorophenoxy]propan-2-yl]-4 H -1,2,4-triazole) to image 11β-HSD1 availability in the human brain with PET. Methods: Fifteen subjects were included in the study. All subjects underwent one two-hour scan following a bolus administration of 11 C-AS2471907. Two subjects underwent an additional scan following blockade with the selective and high affinity 11β-HSD1 inhibitor ASP3662 to evaluate 11 C-AS2471907 non-displaceable distribution volume ( V ND ). Five subjects also underwent an additional scan to evaluate the within-day test-retest variability of 11 C-AS2471907 volumes of distribution ( V T ). Results: 11 C-AS2471907 time-activity curves were best fitted by the two-tissue compartment (2TC) model. 11 C-AS2471907 exhibited a regionally-varying pattern of uptake throughout the brain. The volume of distribution of 11 C-AS2471907 ranged from 3.7 ± 1.5 mL/cm3 in the caudate nucleus to 14.5 ± 5.3 mL/cm3 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 V T ). From the blocking scans, V ND was determined to be 0.16 ± 0.04 mL/cm3 for 11 C-AS2471907. Thus, nearly all uptake was specific and the binding potential ( BP ND ) ranged from 22 in the caudate to 90 in the occipital cortex. Test-retest variability of 2TC V T values was <10% in most large cortical regions (14% in parietal cortex) and ranged from 14% (cerebellum) to 51% (amygdala) in other regions. Intraclass correlation coefficient of 2TC V T values ranged from 0.55 in the white matter to 0.98 in the cerebellum. Conclusion: 11 C-AS2471907 has a very high fraction of specific binding in vivo in humans, and reasonable within-day reproducibility of binding parameters.