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

• Published in: Journal of Nuclear Medicine Vol. 62; no. 4; pp. 561 - 567
• Main Authors: Naganawa, Mika, Li, Songye, Nabulsi, Nabeel, Henry, Shannan, Zheng, Ming-Qiang, Pracitto, Richard, Cai, Zhengxin, Gao, Hong, Kapinos, Michael, Labaree, David, Matuskey, David, Huang, Yiyun, Carson, Richard E.
• Format: Journal Article
• Language: English
• Published: United States 01.04.2021
• Subjects: Adult; Female; GPI-Linked Proteins - metabolism; Healthy Volunteers; Humans; Ligands; Male; Positron-Emission Tomography - adverse effects; Positron-Emission Tomography - methods; Pyridines - adverse effects; Pyridines - metabolism; Pyrrolidinones - adverse effects; Pyrrolidinones - metabolism; Safety; Synaptic Vesicles - metabolism; brain imaging; synaptic density; SV2A; PET; kinetic modeling
• ISSN: 0161-5505; 2159-662X; 1535-5667
• DOI: 10.2967/jnumed.120.249144

The use of synaptic vesicle glycoprotein 2A radiotracers with PET imaging could provide a way to measure synaptic density quantitatively in living humans. C-UCB-J (( )-1-((3-( C-methyl- C)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 C. We developed a new tracer, an F-labeled difluoro-analog of UCB-J ( F-SynVesT-1, also known as F-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-SynVesT-1 and compare with C-UCB-J. Eight healthy volunteers participated in a baseline study of F-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 ( ) and binding potential ( ). 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 Regional time-activity curves were fitted better with the 2TC model than the 1TC model, but 2TC estimates were unstable. The 1TC 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-SynVesT-1 imaging data. The minimum scan time for stable measurement was 60 min. The rank order of and was similar between F-SynVesT-1 and C-UCB-J. Regional was slightly higher for C-UCB-J, but was higher for F-SynVesT-1, though these differences were not significant. Levetiracetam reduced the uptake of F-SynVesT-1 in all regions and produced occupancy of 85.7%. The SUVR-1 of F-SynVesT-1 from 60 to 90 min matched best with 1TC The novel synaptic vesicle glycoprotein 2A tracer, F-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.