First-in-Human Evaluation of ¹⁸F-SynVesT-1, a Radioligand for PET Imaging of Synaptic Vesicle Glycoprotein 2A

The use of synaptic vesicle glycoprotein 2A radiotracers with PET imaging could provide a way to measure synaptic density quantitatively in living humans. ¹¹C-UCB-J ((R)-1-((3-(¹¹C-methyl-¹¹C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), previously developed and assessed in nonhuman primates and humans, showed excellent kinetic properties as a PET radioligand. However, it is labeled with the short half-life isotope ¹¹C. We developed a new tracer, an ¹⁸F-labeled difluoro-analog of UCB-J (¹⁸F-SynVesT-1, also known as ¹⁸F-SDM-8), which displayed favorable properties in monkeys. The purpose of this first-in-human study was to assess the kinetic and binding properties of ¹⁸F-SynVesT-1 and compare with ¹¹C-UCB-J. Methods: Eight healthy volunteers participated in a baseline study of ¹⁸F-SynVesT-1. Four of these subjects were also scanned after a blocking dose of the antiepileptic drug levetiracetam (20 mg/kg). Metabolite-corrected arterial input functions were measured. Regional time-activity curves were analyzed using 1-tissue-compartment (1TC) and 2-tissue-compartment (2TC) models and multilinear analysis 1 to compute total distribution volume (VT) and binding potential (BPND). The centrum semiovale was used as a reference region. The Lassen plot was applied to compute levetiracetam occupancy and nondisplaceable distribution volume. SUV ratio-1 (SUVR-1) over several time windows was compared with BPNDResults: Regional time-activity curves were fitted better with the 2TC model than the 1TC model, but 2TC VT estimates were unstable. The 1TC VT values matched well with those from the 2TC model (excluding the unstable values). Thus, 1TC was judged as the most useful model for quantitative analysis of ¹⁸F-SynVesT-1 imaging data. The minimum scan time for stable VT measurement was 60 min. The rank order of VT and BPND was similar between ¹⁸F-SynVesT-1 and ¹¹C-UCB-J. Regional VT was slightly higher for ¹¹C-UCB-J, but BPND was higher for ¹⁸F-SynVesT-1, though these differences were not significant. Levetiracetam reduced the uptake of ¹⁸F-SynVesT-1 in all regions and produced occupancy of 85.7%. The SUVR-1 of ¹⁸F-SynVesT-1 from 60 to 90 min matched best with 1TC BPNDConclusion: The novel synaptic vesicle glycoprotein 2A tracer, ¹⁸F-SynVesT-1, displays excellent kinetic and in vivo binding properties in humans and holds great potential for the imaging and quantification of synaptic density in neuropsychiatric disorders.