{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T22:30:42Z","timestamp":1784327442343,"version":"3.55.0"},"reference-count":39,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T00:00:00Z","timestamp":1706572800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2024,1,30]]},"abstract":"<jats:p>Background: 11\u03b2-hydroxysteroid dehydrogenase type 1 (11\u03b2-HSD1) regulates intracellular cortisol and its inhibition by the small molecule inhibitor, Xanamem\u2122, may provide a disease-modifying strategy for Alzheimer\u2019s disease (AD). Animal models suggest a range of 30\u201360% enzyme inhibition may suffice to provide neuroprotection. Objective: To determine the regional brain occupancy of 11\u03b2-HSD1 by Xanamem\u2122 in cognitively normal participants (CN) and mild cognitive impairment (MCI)\/mild AD patients to investigate potential dosing ranges for future efficacy studies. Methods: Seventeen MCI\/AD and 23 CN were included. Regional brain time-activity curves (TAC), standardized uptake values (SUV40\u201360) 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 11\u03b2-HSD1 occupancy by increasing doses of Xanamem\u2122 (5\u200amg, 10\u200amg, 20\u200amg or 30\u200amg daily for 7 days). Results: All measures showed high 11\u03b2-HSD1 occupancy with Xanamem to similar degree in CN and MCI\/AD. The dose-response relationship was relatively flat above 5\u200amg. Respective median (interquartile range [Q1-Q3]) 11\u03b2-HSD1 occupancy in the MCI\/AD and CN groups after treatment with 10\u200amg Xanamem were 80% [79\u201381%] and 75% [71\u201376%] in the neocortex, 69% [64\u201370%] and 61% [52\u201363%] in the medial temporal lobe, 80% [79\u201380%] and 73% [68\u201373%] in the basal ganglia, and 71% [67\u201375%] and 66% [62\u201368%] in the cerebellum. Conclusions: TAC, SUV40\u201360, and VT measures indicate Xanamem achieves high target occupancy levels with near saturation at 10\u200amg daily. These data support exploration of doses of\u226410\u200amg daily in future clinical studies.<\/jats:p>","DOI":"10.3233\/jad-220542","type":"journal-article","created":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T11:36:09Z","timestamp":1705664169000},"page":"1463-1475","source":"Crossref","is-referenced-by-count":9,"title":["Brain 11\u03b2-Hydroxysteroid Dehydrogenase Type 1 Occupancy by Xanamem\u2122 Assessed by PET in Alzheimer\u2019s Disease and Cognitively Normal Individuals"],"prefix":"10.1177","volume":"97","author":[{"given":"Victor L.","family":"Villemagne","sequence":"first","affiliation":[{"name":"Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VA, Australia"},{"name":"Department of Psychiatry, The University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Dor\u00e9","sequence":"additional","affiliation":[{"name":"Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VA, Australia"},{"name":"CSIRO e-Health Research Centre, Brisbane, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Chong","sequence":"additional","affiliation":[{"name":"Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kassiou","sequence":"additional","affiliation":[{"name":"The University of Sydney, School of Chemistry, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Mulligan","sequence":"additional","affiliation":[{"name":"Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VA, Australia"},{"name":"Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azadeh","family":"Feizpour","sequence":"additional","affiliation":[{"name":"Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VA, Australia"},{"name":"Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Taylor","sequence":"additional","affiliation":[{"name":"Actinogen Medical, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Roesner","sequence":"additional","affiliation":[{"name":"Actinogen Medical, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Miller","sequence":"additional","affiliation":[{"name":"Actinogen Medical, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C.","family":"Rowe","sequence":"additional","affiliation":[{"name":"Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VA, Australia"},{"name":"Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-220542_ref4","unstructured":"Eisai, Inc. 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impairment","volume":"30","author":"Popp","year":"2009","journal-title":"Neurobiol Aging"},{"key":"10.3233\/JAD-220542_ref40","unstructured":"ClinicalTrials.gov NCT02727699: A Phase II Study to Assess the Safety, Tolerability and Efficacy of Xanamem\u2122 in Subjects With Mild Dementia Due to AD (XanADu), https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02727699?term=X anadu&draw=2&rank=1, Last updated May 6, 2021, Accessed on March 3, 2022."},{"key":"10.3233\/JAD-220542_ref41","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1111\/bph.13699","article-title":"Selection and early clinical evaluation of the brain-penetrant 11\u03b2-hydroxysteroid dehydrogenase type 1 (11\u03b2-HSD1) inhibitor UE2343 (Xanamem)","volume":"174","author":"Webster","year":"2017","journal-title":"Br J Pharmacol"},{"key":"10.3233\/JAD-220542_ref42","unstructured":"ClinicalTrials.gov NCT03830762: Xanamem\u2122 in Healthy Elderly Subjects (XanaHES), 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