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

Abstract

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 (V_T) and binding potential (BP_ND). 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 BP_NDResults: 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 ¹⁸F-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 ¹⁸F-SynVesT-1 and ¹¹C-UCB-J. Regional V_T was slightly higher for ¹¹C-UCB-J, but BP_ND 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 BP_NDConclusion: 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.

Keywords: PET; SV2A; brain imaging; kinetic modeling; synaptic density.

Graphical abstract

FIGURE 1.

Mean ± SD of plasma parent fraction (A) and metabolite-corrected plasma activity (B) in baseline studies and levetiracetam blocking studies with ¹⁸F-SynVesT-1.

FIGURE 2.

Time–activity curves and fittings with 1TC (dotted curve) and 2TC (solid curve) models in same subject under baseline conditions (A and B) and levetiracetam blocking conditions (C and D) with ¹⁸F-SynVesT-1, and under same baseline conditions (E and F) and blocking conditions (G and H) with ¹¹C-UCB-J. 2TC model was not applied to ¹¹C-UCB-J.

FIGURE 3.

MR and coregistered parametric V_T images of ¹⁸F-SynVesT-1 (120-min PET data) and ¹¹C-UCB-J (90-min PET data) in same subject, calculated with 1TC model and basis function method.

FIGURE 4.

Occupancy plots for blocking scans with levetiracetam, 20 mg/kg, measured with ¹⁸F-SynVesT-1 (A) and ¹¹C-UCB-J (B) in same subject. Estimated SV2A occupancy values were 86% in A and 83% in B.

FIGURE 5.

Mean and SD of percentage differences between SUVR-1 from different time windows (30-min duration) and 1TC BP_ND. Each data point was plotted at beginning of each window for SUVR-1 computation.