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. C-11-UCB-J ((R)-1-((3-C-1(1)-methy-C-11)pyrid in -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 C-11. We developed a new tracer, an F-18-labeled difluoro-analog of UCB-J (F-18-SynVesT-1, also known as F-18-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 F-18-SynVesT-1 and compare with C-11-UCB-J. Methods: Eight healthy volunteers participated in a baseline study of F-18-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 (V-T) 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 BPND. Results: Regional time-activity curves were fitted better with the 2TC model than the 1TC model, but 2TC V-T estimates were unstable. The 1TC V-T 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 F-18-SynVesT-1 imaging data. The minimum scan time for stable V-T measurement was 60 min. The rank order of V-T and BP ND was similar between F-18-SynVesT-1 and 11 C-UCB-J. Regional V-T was slightly higher for 11 C-UCB-J, but BP ND was higher for F-18-SynVesT1 , though these differences were not significant. Levetiracetam reduced the uptake of F-18-SynVesT-1 in all regions and produced occupancy of 85.7%. The SUVR-1 of F-18-SynVesT-1 from 60 to 90 min matched best with 1TC BPND. Conclusion: The novel synaptic vesicle glycoprotein 2A tracer, F-18-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.

Automated summary

The novel synaptic vesicle glycoprotein 2A tracer, F-18-SynVesT-1, displays excellent kinetic and in vivo binding properties in humans, showing great potential for imaging and quantification of synaptic density in neuropsychiatric disorders.