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 (V_T) and binding potential (BP_ND). 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 BP_ND. Results: Regional time–activity curves were fitted better with the 2TC model than the 1TC model, but 2TC V_T estimates were unstable. The 1TC V_T 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 V_T measurement was 60 min. The rank order of V_T and BP_ND was similar between ¹⁸F-SynVesT-1 and ¹¹C-UCB-J. Regional V_T was slightly higher for ¹¹C-UCB-J, but BP_ND 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 BP_ND. 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. Visual Abstract

Microglia-mediated synaptic loss contributes to the development of cognitive impairments in Alzheimer’s disease (AD). However, the basis for this immune-mediated attack on synapses remains to be elucidated. Treatment with the metabotropic glutamate receptor 5 (mGluR5) silent allosteric modulator (SAM), BMS-984923, prevents β-amyloid oligomer–induced aberrant synaptic signaling while preserving physiological glutamate response. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [ ¹⁸ F]FPEB positron emission tomography (PET) at doses shown to be safe in rodents and nonhuman primates. In aged mouse models of AD ( APPswe/PS1 Δ E9 overexpressing transgenic and App ^NL-G-F / hMapt double knock-in), SAM treatment fully restored synaptic density as measured by [ ¹⁸ F]SynVesT-1 PET for SV2A and by histology, and the therapeutic benefit persisted after drug washout. Phospho-TAU accumulation in double knock-in mice was also reduced by SAM treatment. Single-nuclei transcriptomics demonstrated that SAM treatment in both models normalized expression patterns to a far greater extent in neurons than glia. Last, treatment prevented synaptic localization of the complement component C1Q and synaptic engulfment in AD mice. Thus, selective modulation of mGluR5 reversed neuronal gene expression changes to protect synapses from damage by microglial mediators in rodents.