Abstract
The use of synaptic vesicle protein 2A (SV2A) radiotracers with positron emission tomography (PET) imaging could provide a way to measure synaptic density quantitatively in living humans. 11C-UCB-J, 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, a.k.a. 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 anti-epileptic drug levetiracetam (20 mg/kg). Metabolite-corrected arterial input functions were measured. Regional time-activity curves (TACs) were analyzed using one- and two-tissue compartment (1TC, 2TC) models and multilinear analysis 1 (MA1) to compute 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 non-displaceable distribution volume (VND). Standardized uptake value ratio (SUVR) -1 over several time windows was compared with BPND. Results: Regional TACs 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. Minimum scan time for stable VT measurement was 60 min. The rank order of VT and BPND values was similar between 18F-SynVesT-1 and 11C-UCB-J. Regional VT values were slightly higher for 11C-UCB-J, but BPND values were 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%. SUVR-1 of 18F-SynVesT-1 from 60-90 min matched best with 1TC BPND. Conclusion: The novel SV2A 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.
- Molecular Imaging
- PET
- Radiotracer Tissue Kinetics
- Brain imaging
- Kinetic modeling
- Positron emission tomography
- SV2A
- Synaptic density
- Copyright © 2020 by the Society of Nuclear Medicine and Molecular Imaging, Inc.