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Synaptic vesicle glycoprotein 2A (SV2A), whose availability is quantifiable by [\u00b9\u2078F]SynVesT-1 positron emission tomography (PET), is commonly interpreted as a proxy for synaptic density. In this randomized study, we examined 40 healthy adults (mean age 27.5\u2009\u00b1\u20096.5 years) who underwent two [\u00b9\u2078F]SynVesT-1 PET scans on consecutive days. Half of the participants were assigned to the normal sleep (i.e., control) condition and half to the sleep deprivation condition. Scans were performed at the same circadian time point, approximately 4 h after awakening in the control group and during baseline in the sleep deprivation group or after ~28 h of continuous wakefulness in the sleep deprivation group after sleep deprivation. Sleep deprivation led to significant increases in synaptic vesicle glycoprotein 2A binding in multiple brain regions, including the thalamus (+4.6%), hippocampus (+5.6%), and parietal cortex (+3.2%), whereas no changes were observed in controls. The degree of increase in synaptic vesicle glycoprotein 2A positively correlated with elevated slow wave activity during recovery sleep, a physiological marker of sleep pressure. These findings provide in vivo support for the synaptic homeostasis hypothesis in humans and suggest that synaptic vesicle glycoprotein 2A PET imaging is sensitive to sleep-wake dependent synaptic plasticity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec001\">\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>\n                      The study was prospectively registered on 19.01.2022 here: German Clinical Trials Registry: DRKS # DRKS00027867,\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/drks.de\/search\/en\/trial\/DRKS00027867\" xlink:type=\"simple\">https:\/\/drks.de\/search\/en\/trial\/DRKS00027867<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  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