First-in-Human Evaluation of 18 F-SynVesT-1, a Radioligand for PET Imaging of Synaptic Vesicle Glycoprotein 2A
Open accessAbstract
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 (VT) 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 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. The minimum scan time for stable VT measurement was 60 min. The rank order of VT and BPND was similar between 18F-SynVesT-1 and 11C-UCB-J. Regional VT was slightly higher for 11C-UCB-J, but BPND 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 BPND. Conclusion: 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.
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[18F]SynVesT-1 and [18F]SynVesT-2 extend accessibility through longer half-life, favorable kinetics, and validated simplified quantification protocols suited to clinical workflows.
“[11C]UCB-J established high brain uptake and specificity, creating the benchmark for human and preclinical studies, while [18F]SynVesT-1 and [18F]SynVesT-2 extend accessibility through longer half-life, favorable kinetics, and validated simplified quantification protocols suited to clinical workflows [174,208,209].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [174]
The Conclusion supports longer half-life, favorable kinetics, and a short-scan quantification method for ¹⁸F-SynVesT-1. The Discussion says its simplified SUVR-1 method was assessed in healthy control baseline scans and may be affected by disease or drug administration. These passages do not establish the same properties or protocol validation for ¹⁸F-SynVesT-2. (LLM, conf=0.87)
Experimental — accuracy not yet measured[11C]UCB-J established high brain uptake and specificity, creating the benchmark for human and preclinical studies.
“[11C]UCB-J established high brain uptake and specificity, creating the benchmark for human and preclinical studies, while [18F]SynVesT-1 and [18F]SynVesT-2 extend accessibility through longer half-life, favorable kinetics, and validated simplified quantification protocols suited to clinical workflows [174,208,209].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [174]
18F-SynVesT-1 is a fluoride ligand measuring synaptic density that has been recently developed.
“In parallel a fluoride ligand measuring synaptic density 18F-SynVesT-1 has been recently developed [202].”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [202]
In humans, [18F]SynVesT-1 displayed outstanding characteristics: very high brain uptake, fast and reversible kinetics, excellent test-retest reproducibility and binding specificity to SV2A.
“In humans, [ 18 F]SynVesT-1 displayed outstanding characteristics, i.e., very high brain uptake, fast and reversible kinetics, excellent test-retest reproducibility and binding specificity to SV2A”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [125]
In comparison to [11C]UCB-J, [18F]SynVesT-1 displayed higher binding potential.
“In comparison to [ 11 C]UCB-J, [ 18 F]SynVesT-1 displayed higher binding potential”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [125]
Excellent test-retest reproducibility and low noise VT images can be obtained.
“Excellent test-retest reproducibility and low noise V T images can be obtained”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [125]
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- Authors
- Naganawa, M., Li, S., Nabulsi, N., Henry, S., Zheng, M.-Q., Pracitto, R., Cai, Z., Gao, H., Kapinos, M., Labaree, D., Matuskey, D., Huang, Y., & Carson, R. E.
- Affiliations
- Yale University (US)
- ORCID
- Venue
- Journal of Nuclear Medicine
- Publisher
- Society of Nuclear Medicine
- Published
- 2020-08-28
- Volume
- 62
- Issue
- 4
- Pages
- 561-567
- ISSN
- 0161-5505 (ISSN-L)
- 2159-662X
- PMC
- PMC8049363
- OpenAlex
- W3082957830
- Cited by
- 138
- References
- 25
- Citations by year
- 2026: 26 · 2025: 29 · 2024: 30 · 2023: 21 · 2022: 22 · 2021: 9 · 2020: 1
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Nuclear Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Yale University
- National Institutes of Health (UL1TR001863)
- National Institute on Aging (R01AG052560, R01AG065474, P30AG066508)
- National Institute of Neurological Disorders and Stroke (R01NS123183)
- National Center for Research Resources (UL1RR024139)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- [11C]UCB-J, SV2A, synaptic density, PET radiotracer, 18F-labeled radiotracer, binding potential, volume of distribution, first-in-human study
- MeSH terms
- Adult, Female, Humans, Ligands, Male, Pyridines, Pyrrolidinones, Safety, Synaptic Vesicles, Positron-Emission Tomography, GPI-Linked Proteins, Healthy Volunteers
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