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

Abstract

The use of synaptic vesicle protein 2A (SV2A) radiotracers with positron emission tomography (PET) imaging could provide a way to measure synaptic density quantitatively in living humans. 11 C-UCB-J, 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 11 C. We developed a new tracer, an 18 F-labeled difluoro-analog of UCB-J ( 18 F-SynVesT-1, a.k.a. 18 F-SDM-8), which displayed favorable properties in monkeys. The purpose of this first-inhuman study was to assess the kinetic and binding properties of 18 F-SynVesT-1 and compare with 11 C-UCB-J.Methods: Eight healthy volunteers participated in a baseline study of 18 F-SynVesT-1. Four of these subjects were also scanned after a blocking dose of the anti-epileptic drug levetiracetam (20 mg/kg).Metabolite-corrected arterial input functions were measured. Regional time-activity curves (TACs) were analyzed using one-and two-tissue compartment (1TC, 2TC) models and multilinear analysis 1 (MA1) to compute 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 non-displaceable distribution volume (V ND ). Standardized uptake value ratio (SUVR) -1 over several time windows was compared with BP ND . Results: Regional TACs 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 18 F-SynVesT-1 imaging data. Minimum scan time for stable V T measurement was 60 min. The rank order of V T and BP ND values was similar between 18 F-SynVesT-1 and 11 C-UCB-J.Regional V T values were slightly higher for 11 C-UCB-J, but BP ND values were higher for 18 F-SynVesT-1, though these differences were not significant. Levetiracetam reduced the uptake of 18 F-SynVesT-1 in all regions and produced occupancy of 85.7%. SUVR-1 of 18 F-SynVesT-1 from 60-90 min matched best with 1TC BP ND . Conclusion:The novel SV2A tracer, 18 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.

The pharmacokinetics of [18F]UCB-H revisited in the healthy non-human primate brain

“…Interestingly, all authors reported issues with 2TCM similar to those reported here, namely lack of convergence or large standard error for V T [14,35,36,39], with large uncertainty on k 4 and values close to 0 [14,35]. As a consequence, 1TCM for [ 11 C]UCB-J and [ 18 F]SynVesT-1 [14,35], and Logan graphical analysis for [ 11 C]UCB-A [39] was selected as method of choice. We reported here similar issues with the use of 2TCM for [ 18 F]UCB-H. We obtained similar AIC for reversible or irreversible 2TCM, and spectral analysis indicated a component at the edge of the frequency range (data not shown), suggesting a small slow component for [ 18 F]UCB-H.…”

“…Brain kinetics of SV2A ligands [ 11 C]UCB-J [35,36] and [ 18 F]SynVesT-1 (a.k.a [ 18 F]SDM-8, [ 18 F]MNI-1126) [14] have been reported as better described by 2TCM in human, but were better modeled with 1TCM in cynomolgus or rhesus monkeys [24,37,38], and [ 11 C]UCB-A was better described with 1TCM at baseline in pigs but 2TCM was required after blocking of the specific signal [39]. Interestingly, all authors reported issues with 2TCM similar to those reported here, namely lack of convergence or large standard error for V T [14,35,36,39], with large uncertainty on k 4 and values close to 0 [14,35]. As a consequence, 1TCM for [ 11 C]UCB-J and [ 18 F]SynVesT-1 [14,35], and Logan graphical analysis for [ 11 C]UCB-A [39] was selected as method of choice.…”

“…With the aim of a better understanding of the role of SV2A in epilepsy and of studying SV2A in diseases of the central nervous system, several SV2A-specific ligands have been developed [9], [ 18 F]UCB-H being one of the first to be labelled [10], subsequently characterized in the rodent [10,11], and in the human brain [12]. The demonstration of the colocalization of SV2A with other synaptic markers using [ 11 C]-UCB-J [13], showed the potential of in vivo imaging of the synaptic density using Positron Emission Tomography (PET), and led recently to the development of new [ 18 F]-labelled ligands [9,[14][15][16][17][18][19]. Preclinical characterization of [ 18 F]UCB-H has mostly been done in the rodent brain [20][21][22], while in non-human primates (NHP) limited data is available [23,24].…”

A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: Synthesis and preclinical characterization of [18F]SDM-16

“…A quantitative tool to image the CNS-PNS synaptic axis will open the opportunity to study the interplay between brain, spinal cord and peripheral nervous system, under normal and disease conditions. We have previously reported the synthesis and evaluation of a series of fluorine-18-labeled SV2A PET tracers, which all showed excellent brain imaging properties, and some have been translated into first-in-human studies [37,42,43]. However, these PET tracers are metabolically labile, with less than 50% parent fraction at 30 min post injection.…”

PET Neuroimaging of Alzheimer's Disease: Radiotracers and Their Utility in Clinical Research

“…Traditionally, synapses can only be observed by electron microscopic and immunohistochemical examinations in biopsy and autopsy tissue samples. Recently a series of novel PET radiotracers selectively targeting SV2A have been developed ( Figure 8 ) (Mercier et al, 2014 ; Estrada et al, 2016 ; Nabulsi et al, 2016 ; Becker et al, 2017 ; Li et al, 2019 ; Cai et al, 2020a ), enabling non-invasive observation and quantification of synaptic density in humans (Finnema et al, 2016 ; Bahri et al, 2017 ; Cai et al, 2020b ; Naganawa et al, 2020b ).…”