First-In-Human Evaluation Of F-18-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.