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The recently developed novel synaptic vesicle 2A protein (SV2A) PET\u2010tracer UCB\u2010J has shown great promise in tracking synaptic loss in AD. However, there have been discrepancies between the findings and a lack of mechanistic insight.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Here we report the first extensive pre\u2010clinical validation studies for UCB\u2010J in control (CN; <jats:italic>n<\/jats:italic>\u00a0=\u00a011) and AD (<jats:italic>n<\/jats:italic>\u00a0=\u00a011) brains using a multidimensional approach of post\u2010mortem brain imaging techniques, radioligand binding, and biochemical studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS AND DISCUSSION<\/jats:title><jats:p>We demonstrate that UCB\u2010J could target SV2A protein with high specificity and depict synaptic loss at synaptosome levels in AD brain regions compared to CNs. UCB\u2010J showed highest synaptic loss in AD hippocampus followed in descending order by frontal cortex, temporal cortex, parietal cortex, and cerebellum. <jats:sup>3<\/jats:sup>H\u2010UCB\u2010J large brain\u2010section autoradiography and cellular\/subcellular fractions binding studies indicated potential off\u2010target interaction with phosphorylated tau (p\u2010tau) species in AD brains, which could have subsequent clinical implications for imaging studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Synaptic positron emission tomography (PET)\u2013tracer UCB\u2010J could target synaptic vesicle 2A protein (SV2A) with high specificity in Alzheimer's disease (AD) and control brains.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Synaptic PET\u2010tracer UCB\u2010J could depict synaptic loss at synaptosome levels in AD brain regions compared to control.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Potential off\u2010target interaction of UCB\u2010J with phosphorylated tau (p\u2010tau) species at cellular\/subcellular levels could have subsequent clinical implications for imaging studies, warranting further investigations.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.13720","type":"journal-article","created":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T07:00:16Z","timestamp":1708066816000},"page":"2589-2605","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Tracing synaptic loss in Alzheimer's brain with SV2A PET\u2010tracer UCB\u2010J"],"prefix":"10.1002","volume":"20","author":[{"given":"Amit","family":"Kumar","sequence":"first","affiliation":[{"name":"Division of Clinical Geriatrics Center for Alzheimer Research Department of Neurobiology Care Sciences and Society Karolinska Institutet  Stockholm 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