First-in-Human Study of 18F-SynVesT-2: An SV2A PET Imaging Probe with Fast Brain Kinetics and High Specific Binding

Lindsey R Drake; Yanjun Wu; Mika Naganawa; Ruth Asch; Chao Zheng; Soheila Najafzadeh; Richard Pracitto; Marcel Lindemann; Songye Li; Jim Ropchan; David Labaree; Paul R Emery; Mark Dias; Shannan Henry; Nabeel Nabulsi; David Matuskey; Ansel T Hillmer; Jean-Dominique Gallezot; Richard E Carson; Zhengxin Cai; Yiyun Huang

doi:10.2967/jnumed.123.266470

First-in-Human Study of ¹⁸F-SynVesT-2: An SV2A PET Imaging Probe with Fast Brain Kinetics and High Specific Binding

J Nucl Med. 2024 Feb 15;65(3):462-469. doi: 10.2967/jnumed.123.266470. Online ahead of print.

Authors

Lindsey R Drake¹, Yanjun Wu¹, Mika Naganawa¹, Ruth Asch¹, Chao Zheng¹, Soheila Najafzadeh¹, Richard Pracitto¹, Marcel Lindemann¹, Songye Li¹, Jim Ropchan¹, David Labaree¹, Paul R Emery¹, Mark Dias¹, Shannan Henry¹, Nabeel Nabulsi¹, David Matuskey¹, Ansel T Hillmer¹, Jean-Dominique Gallezot¹, Richard E Carson¹, Zhengxin Cai², Yiyun Huang

Affiliations

¹ Yale PET Center, New Haven, Connecticut.
² Yale PET Center, New Haven, Connecticut henry.huang@yale.edu jason.cai@yale.edu.

PMID: 38360052
PMCID: PMC10924160 (available on 2024-09-01)
DOI: 10.2967/jnumed.123.266470

Abstract

PET imaging of synaptic vesicle glycoprotein 2A allows for noninvasive quantification of synapses. This first-in-human study aimed to evaluate the kinetics, test-retest reproducibility, and extent of specific binding of a recently developed synaptic vesicle glycoprotein 2A PET ligand, (R)-4-(3-(¹⁸F-fluoro)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidine-2-one (¹⁸F-SynVesT-2), with fast brain kinetics. Methods: Nine healthy volunteers participated in this study and were scanned on a High Resolution Research Tomograph scanner with ¹⁸F-SynVesT-2. Five volunteers were scanned twice on 2 different days. Five volunteers were rescanned with preinjected levetiracetam (20 mg/kg, intravenously). Arterial blood was collected to calculate the plasma free fraction and generate the arterial input function. Individual MR images were coregistered to a brain atlas to define regions of interest for generating time-activity curves, which were fitted with 1- and 2-tissue-compartment (1TC and 2TC) models to derive the regional distribution volume (V _T). The regional nondisplaceable binding potential (BP _ND) was calculated from 1TC V _T, using the centrum semiovale (CS) as the reference region. Results: ¹⁸F-SynVesT-2 was synthesized with high molar activity (187 ± 69 MBq/nmol, n = 19). The parent fraction of ¹⁸F-SynVesT-2 in plasma was 28% ± 8% at 30 min after injection, and the plasma free fraction was high (0.29 ± 0.04). ¹⁸F-SynVesT-2 entered the brain quickly, with an SUV_peak of 8 within 10 min after injection. Regional time-activity curves fitted well with both the 1TC and the 2TC models; however, V _T was estimated more reliably using the 1TC model. The 1TC V _T ranged from 1.9 ± 0.2 mL/cm³ in CS to 7.6 ± 0.8 mL/cm³ in the putamen, with low absolute test-retest variability (6.0% ± 3.6%). Regional BP _ND ranged from 1.76 ± 0.21 in the hippocampus to 3.06 ± 0.29 in the putamen. A 20-min scan was sufficient to provide reliable V _T and BP _ND Conclusion: ¹⁸F-SynVesT-2 has fast kinetics, high specific uptake, and low nonspecific uptake in the brain. Consistent with the nonhuman primate results, the kinetics of ¹⁸F-SynVesT-2 is faster than the kinetics of ¹¹C-UCB-J and ¹⁸F-SynVesT-1 in the human brain and enables a shorter dynamic scan to derive physiologic information on cerebral blood flow and synapse density.

Keywords: 18F-SynVesT-2; SV2A; brain PET; dosimetry; first-in-human; kinetic modeling.