Preclinical validation and kinetic modelling of the SV2A PET ligand [ 18 F]UCB-J in mice

Abstract

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 [¹¹C]UCB-J has high binding affinity and selectivity for SV2A but has a short physical half-life due to the ¹¹C isotope. Here we report the characterization and validation of its ¹⁸F-labeled equivalent, [¹⁸F]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). [¹⁸F]UCB-J showed relatively fast kinetics and a reliable measure of the IDIF-based volume of distribution (V_T(IDIF)). [¹⁸F]UCB-J specificity for SV2A was confirmed through a levetiracetam blocking assay (50 to 200 mg/kg). Reproducibility of the V_T(IDIF) was determined through test-retest analysis, revealing significant correlation (r² = 0.773, p < 0.0001). Time-stability analyses indicate a scan duration of 60 min to be sufficient to obtain a reliable V_T(IDIF). In conclusion, [¹⁸F]UCB-J is a selective SV2A ligand with optimal kinetics in mice. Further investigation is warranted for (pre)clinical applicability of [¹⁸F]UCB-J in synaptopathies.