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Extensive evidence suggests that amyloid beta (A\u03b2) is central to AD pathophysiology, and A\u03b2 oligomers are among the most toxic forms of A\u03b2. CT1812 is a novel brain penetrant sigma-2 receptor ligand that interferes with the binding of A\u03b2 oligomers to neurons. Preclinical studies of CT1812 have demonstrated its ability to displace A\u03b2 oligomers from neurons, restore synapses in cell cultures, and improve cognitive measures in mouse models of AD. CT1812 was found to be generally safe and well tolerated in a placebo-controlled phase 1 clinical trial in healthy volunteers and phase 1a\/2 clinical trials in patients with mild to moderate dementia due to AD. The unique objective of this study was to incorporate synaptic positron emission tomography (PET) imaging as an outcome measure for CT1812 in AD patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The present phase 1\/2 study was a randomized, double-blind, placebo-controlled, parallel-group trial conducted in 23 participants with mild to moderate dementia due to AD to primarily evaluate the safety of CT1812 and secondarily its pharmacodynamic effects. Participants received either placebo or 100\u00a0mg or 300\u00a0mg per day of oral CT1812 for 24\u00a0weeks. Pharmacodynamic effects were assessed using the exploratory efficacy endpoints synaptic vesicle glycoprotein 2A (SV2A) PET, fluorodeoxyglucose (FDG) PET, volumetric MRI, cognitive clinical measures, as well as cerebrospinal fluid (CSF) biomarkers of AD pathology and synaptic degeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>No treatment differences relative to placebo were observed in the change from baseline at 24\u00a0weeks in either SV2A or FDG PET signal, the cognitive clinical rating scales, or in CSF biomarkers. Composite region volumetric MRI revealed a trend towards tissue preservation in participants treated with either dose of CT1812, and nominally significant differences with both doses of CT1812 compared to placebo were found in the pericentral, prefrontal, and hippocampal cortices. CT1812 was safe and well tolerated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The safety findings of this 24-week study and the observed changes on volumetric MRI with CT1812 support its further clinical development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>The clinical trial described in this manuscript is registered at clinicaltrials.gov (NCT03493282).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13195-024-01382-2","type":"journal-article","created":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T06:03:43Z","timestamp":1706162623000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"16","author":[{"given":"Christopher H.","family":"van Dyck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam P.","family":"Mecca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan S.","family":"O\u2019Dell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugh H.","family":"Bartlett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina G.","family":"Diepenbrock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Hamby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Grundman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Catalano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony O.","family":"Caggiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard E.","family":"Carson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,25]]},"reference":[{"key":"1382_CR1","doi-asserted-by":"publisher","first-page":"e12295","DOI":"10.1002\/trc2.12295","volume":"8","author":"J Cummings","year":"2022","unstructured":"Cummings J, Lee G, Nahed P, et al. 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