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Title: | Brain 11β-Hydroxysteroid Dehydrogenase Type 1 Occupancy by Xanamem™ Assessed by PET in Alzheimer's Disease and Cognitively Normal Individuals. | Austin Authors: | Villemagne, Victor L ;Doré, Vincent ;Chong, Lee;Kassiou, Michael;Mulligan, Rachel S ;Feizpour, Azadeh;Taylor, Jack;Roesner, Miriam;Miller, Tamara;Rowe, Christopher C | Affiliation: | Molecular Imaging and Therapy CSIRO e-Health Research Centre, Brisbane, Queensland, Australia. The University of Sydney, School of Chemistry, Sydney, Australia. Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia. Actinogen Medical, Sydney, New South Wales, Australia. |
Issue Date: | 19-Jan-2024 | Date: | 2024 | Publication information: | Journal of Alzheimer's Disease : JAD 2024; 97(3) | Abstract: | 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates intracellular cortisol and its inhibition by the small molecule inhibitor, Xanamem™, may provide a disease-modifying strategy for Alzheimer's disease (AD). Animal models suggest a range of 30-60% enzyme inhibition may suffice to provide neuroprotection. To determine the regional brain occupancy of 11β-HSD1 by Xanamem™ in cognitively normal participants (CN) and mild cognitive impairment (MCI)/mild AD patients to investigate potential dosing ranges for future efficacy studies. Seventeen MCI/AD and 23 CN were included. Regional brain time-activity curves (TAC), standardized uptake values (SUV40-60) and volume of distribution (VT) from Logan plot with image derived input function from 11C-TARACT positron emission tomography (PET) were used to assess the degree of 11β-HSD1 occupancy by increasing doses of Xanamem™ (5 mg, 10 mg, 20 mg or 30 mg daily for 7 days). All measures showed high 11β-HSD1 occupancy with Xanamem to similar degree in CN and MCI/AD. The dose-response relationship was relatively flat above 5 mg. Respective median (interquartile range [Q1-Q3]) 11β-HSD1 occupancy in the MCI/AD and CN groups after treatment with 10 mg Xanamem were 80% [79-81%] and 75% [71-76%] in the neocortex, 69% [64-70%] and 61% [52-63%] in the medial temporal lobe, 80% [79-80%] and 73% [68-73%] in the basal ganglia, and 71% [67-75%] and 66% [62-68%] in the cerebellum. TAC, SUV40-60, and VT measures indicate Xanamem achieves high target occupancy levels with near saturation at 10 mg daily. These data support exploration of doses of≤10 mg daily in future clinical studies. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/35019 | DOI: | 10.3233/JAD-220542 | ORCID: | Journal: | Journal of Alzheimer's Disease : JAD | PubMed URL: | 38250767 | ISSN: | 1875-8908 | Type: | Journal Article | Subjects: | 11beta-hydroxysteroid dehydrogenase type 1 Alzheimer’s disease cortisol drug development positron emission tomography target occupancy |
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