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

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, ()-4-(3-(F-fluoro)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidine-2-one (F-SynVesT-2), with fast brain kinetics. Nine healthy volunteers participated in this study and were scanned on a High Resolution Research Tomograph scanner with F-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 ( ). The regional nondisplaceable binding potential ( ) was calculated from 1TC , using the centrum semiovale (CS) as the reference region. F-SynVesT-2 was synthesized with high molar activity (187 ± 69 MBq/nmol, = 19). The parent fraction of F-SynVesT-2 in plasma was 28% ± 8% at 30 min after injection, and the plasma free fraction was high (0.29 ± 0.04). F-SynVesT-2 entered the brain quickly, with an SUV of 8 within 10 min after injection. Regional time-activity curves fitted well with both the 1TC and the 2TC models; however, was estimated more reliably using the 1TC model. The 1TC ranged from 1.9 ± 0.2 mL/cm in CS to 7.6 ± 0.8 mL/cm in the putamen, with low absolute test-retest variability (6.0% ± 3.6%). Regional 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 and F-SynVesT-2 has fast kinetics, high specific uptake, and low nonspecific uptake in the brain. Consistent with the nonhuman primate results, the kinetics of F-SynVesT-2 is faster than the kinetics of C-UCB-J and F-SynVesT-1 in the human brain and enables a shorter dynamic scan to derive physiologic information on cerebral blood flow and synapse density.