Validation and noninvasive kinetic modeling of [¹¹C]UCB-J PET imaging in mice

Abstract

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. <i>V</i>_{T (IDIF)} values estimated with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, <i>p</i> < 0.0001), with 1TCM performing better than 2TCM for <i>K</i>_{1 (IDIF)}. A scan duration of 60 min was sufficient for reliable <i>V</i>_{T (IDIF)} and <i>K</i>_{1 (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.