In vivo imaging of synaptic density with [11C]UCB-J PET in two mouse models of neurodegenerative disease

The positron emission tomography (PET) radioligand [C-11]UCB-J binds to synaptic vesicle protein 2A (SV2A) and is used to investigate synaptic density in the living brain. Clinical studies have indicated reduced [C-11]UCB-J binding in Alzheimer's disease (AD) and Parkinson's disease (PD) brains compared to healthy controls. Still, it is unknown whether [C-11]UCB-J PET can visualise synaptic loss in mouse models of these disorders. Such models are essential for understanding disease pathology and for evaluating the effects of novel disease-modifying drug candidates. In the present study, synaptic density in transgenic models of AD (ArcSwe) and PD (L61) was stud-ied using [C-11]UCB-J PET. Data were acquired during 60 min after injection, and time-activity curves (TACs) in different brain regions and the left ventricle of the heart were generated based on the dynamic PET images. The [C-11]UCB-J brain concentrations were expressed as standardised uptake value (SUV) over time. The area under the SUV curve (AUC), the ratio of AUC in the brain to that in the heart (AUCbrain/blood), and the volume of distribution (VT) obtained by kinetic modelling using the heart TAC as input were compared between trans-genic and age-matched wild type (WT) mice. The L61 mice displayed 11-13% lower AUCbrain/blood ratio and brain VT generated by kinetic modeling compared to the control WT mice. In general, also transgenic ArcSwe mice tended to show lower [C-11]UCB-J brain exposure than age-matched WT controls, but variation within the different animal groups was high. Older WT mice (18-20 months) showed lower [C-11]UCB-J brain exposure than younger WT mice (8-9 months). Together, these data imply that [C-11]UCB-J PET reflects synaptic density in mouse models of neurodegeneration and that inter-subject variation is large. In addition, the study suggested that model-independent AUCbrain/blood ratio can be used to evaluate [C-11]UCB-J binding as an alternative to full pharmacokinetic modelling.

Automated summary

The study investigated synaptic density in transgenic mouse models of Alzheimer's disease and Parkinson's disease using [C-11]UCB-J PET, suggesting that the PET imaging reflects synaptic density in mouse models of neurodegeneration with large inter-subject variation. Additionally, the study proposed that the model-independent AUCbrain/blood ratio can be used to evaluate [C-11]UCB-J binding as an alternative to full pharmacokinetic modeling.