Autoradiographic assessment of SynVesT-1 revealed changes in non-displaceable binding with demyelination and remyelination: implications for SV2A PET analysis

Changes in synaptic density and function have been observed in a range of neurological disorders and are important determinants of disease progression and severity(1). Synaptic vesicle glycoprotein 2A (SV2A) is involved in the regulation of neurotransmitter release and is expressed in both excitatory and inhibitory synapse subtypes throughout the brain, making it a promising biomarker for assessing synaptic integrity(2,3). The use of positron emission tomography (PET) radioligands targeting SV2A has enabled in vivo visualisation of synaptic alterations(4). In particular, [18F]SynVestT-1 has displayed excellent imaging and binding characteristics across various species, including mice, rats, non-human primates, and humans(5–9). Although it has also been tested in a number of neurodegenerative and neuropsychiatric disorders(10,11), variations in its binding dynamics under disease conditions and how those may contribute to reported outcome measures remain insufficiently characterised.<br/>The cuprizone model is an established mouse model of global brain demyelination and remyelination. Loss of myelin occurs after 6 weeks of cuprizone administration, with significant remyelination occurring after discontinuation. While commonly used as a multiple sclerosis model, it is also characterised by pathology observed in many neurodegenerative diseases: myelin loss, axonal loss, glial cell-mediated inflammation, and alterations in synaptic density and plasticity(12,13). <br/>In this study, we tested [3H]SynVesT-1 in vitro using autoradiography due to its longer half-life and higher spatial resolution compared with [18F]SynVestT-1. We aimed to characterise its binding properties and how they are altered in demyelination and subsequent remyelination in this model. Understanding the extent to which pathological changes impact tracer behaviour will have important implications for interpreting in vivo PET imaging results using [18F]SynVesT-1.<br/>