Preclinical validation and kinetic modelling of the SV2A PET ligand [F]UCB-J in mice.

Synaptic vesicle protein 2A (SV2A) is ubiquitously expressed in presynaptic terminals where it functions as a neurotransmission regulator protein. Synaptopathy has been reported during healthy ageing and in a variety of neurodegenerative diseases. Positron emission tomography (PET) imaging of SV2A can be used to evaluate synaptic density. The PET ligand [C]UCB-J has high binding affinity and selectivity for SV2A but has a short physical half-life due to the C isotope. Here we report the characterization and validation of its F-labeled equivalent, [F]UCB-J, in terms of specificity, reproducibility and stability in C57BL/6J mice. Plasma analysis revealed at least one polar radiometabolite. Kinetic modelling was performed using a population-based metabolite corrected image-derived input function (IDIF). [F]UCB-J showed relatively fast kinetics and a reliable measure of the IDIF-based volume of distribution (). [F]UCB-J specificity for SV2A was confirmed through a levetiracetam blocking assay (50 to 200 mg/kg). Reproducibility of the was determined through test-retest analysis, revealing significant correlation (r = 0.773,  < 0.0001). Time-stability analyses indicate a scan duration of 60 min to be sufficient to obtain a reliable . In conclusion, [F]UCB-J is a selective SV2A ligand with optimal kinetics in mice. Further investigation is warranted for (pre)clinical applicability of [F]UCB-J in synaptopathies.