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

Abstract

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 ¹¹C-AS2471907 (3-(2-chlorophenyl)-4-(methyl-¹¹<i>C</i>)-5-[2-[2,4,6-trifluorophenoxy]propan-2-yl]-4<i>H</i>-1,2,4-triazole) to image 11β-HSD1 availability in the human brain with PET. <b>Methods:</b> Fifteen subjects were included in the study. All subjects underwent one 2-h scan after a bolus administration of ¹¹C-AS2471907. Two subjects underwent an additional scan after blockade with the selective and high-affinity 11β-HSD1 inhibitor ASP3662 to evaluate ¹¹C-AS2471907 nondisplaceable distribution volume. Five subjects also underwent an additional scan to evaluate the within-day test-retest variability of ¹¹C-AS2471907 volumes of distribution (<i>V</i>_T). <b>Results:</b>¹¹C-AS2471907 time-activity curves were best fitted by the 2-tissue-compartment (2TC) model. ¹¹C-AS2471907 exhibited a regionally varying pattern of uptake throughout the brain. The <i>V</i>_T of ¹¹C-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 <i>V</i>_T). From the blocking scans, nondisplaceable distribution volume was determined to be 0.16 ± 0.04 mL/cm³ for ¹¹C-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 <i>V</i>_T 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 <i>V</i>_T values ranged from 0.55 in the white matter to 0.98 in the cerebellum. <b>Conclusion:</b>¹¹C-AS2471907 has a high fraction of specific binding in vivo in humans and reasonable within-day reproducibility of binding parameters.