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Measuring synaptic density in mice

PET imaging of Synaptic Vesicle Glycoprotein 2A (SV2A) may be a biomarker of synaptic plasticity. This work validated preclinical method for full quantitation in mice, the most commonly used research model.




Synaptic density in mice quantified with 11C-UCB-J

Synaptic pathology is associated with several brain disorders, thus positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) using the radioligand [11C]UCB-J may provide a tool to measure synaptic alterations. Given the pivotal role of mouse models in understanding neuropsychiatric and neurodegenerative disorders, this study aims to validate and characterize [11C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examined kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metabolism. Regional TACs during baseline showed rapid uptake of [11C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. VT (IDIF) values estimated with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r¼0.999, p < 0.0001), with 1TCM performing better than 2TCM for K1 (IDIF). A scan duration of 60 min was sufficient for reliable VT (IDIF) and K1 (IDIF) estimations. In vivo metabolism of [11C]UCB-J was relatively rapid, with a parent fraction of 22.5 4.2% at 15 min p.i. In conclusion, our findings show that [11C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic density in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.



Importance/Impact


“Full quantitation is necessary to understand changes in receptor density in living organisms as a result of disease or of therapeutic intervention. Validating quantitation without blood sampling in small animals is challenging, and this work enables longitudinal study in mice using this tracer”

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Contact

Christopher Cawthorne
Flanders BioImaging Co-ordinator

O&N I Herestraat 49 - box 505
3000 Leuven
Belgium
room: 05.616

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Tel: 0032-16-325694

christopher.cawthorne@kuleuven.be

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