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

Abstract

Purpose To quantify the synaptic vesicle glycoprotein 2A (SV2A) changes in the whole central nervous system (CNS) under pathophysiological conditions, a high affinity SV2A PET radiotracer with improved in vivo stability is desirable to minimize the potential confounding effect of radiometabolites. The aim of this study was to develop such a PET tracer based on the molecular scaffold of UCB-A, and evaluate its pharmacokinetics, in vivo stability, specific binding, and nonspecific binding signals in nonhuman primate brains, in comparison with [11C]UCB-A, [11C]UCB-J, and [18F]SynVesT-1. Methods The racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one) and its two enantiomers were synthesized and assayed for in vitro binding affinities to human SV2A. We synthesized the enantiopure [18F]SDM-16 using the corresponding enantiopure arylstannane precursor. Nonhuman primate brain PET scans were performed on FOCUS 220 scanners. Arterial blood was drawn for the measurement of plasma free fraction (fP), radiometabolite analysis, and construction of the plasma input function. Regional time-activity curves (TACs) were fitted with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Nondisplaceable binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region. Results SDM-16 was synthesized in 3 steps with 44% overall yield and has the highest affinity (Ki = 0.9 nM) to human SV2A among all reported SV2A ligands. [18F]SDM-16 was prepared in about 20% decay-corrected radiochemical yield within 90 min, with greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in monkey brains and was metabolically more stable than the other SV2A PET tracers. The fP of [18F]SDM-16 was 69%, which was higher than those of [11C]UCB-J (46%), [18F]SynVesT-1 (43%), [18F]SynVesT-2 (41%), and [18F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test–retest variability (TRV) was 7 ± 3%, and averaged absolute TRV (aTRV) was 14 ± 7% for the analyzed brain regions. Conclusion We have successfully synthesized a novel SV2A PET tracer [18F]SDM-16, which has the highest SV2A binding affinity and metabolical stability among published SV2A PET tracers. The [18F]SDM-16 brain PET images showed superb contrast between gray matter and white matter. Moreover, [18F]SDM-16 showed high specific and reversible binding in the NHP brains, allowing for the reliable and sensitive quantification of SV2A, and has potential applications in the visualization and quantification of SV2A beyond the brain.

Synaptic Vesicle Glycoprotein 2A: Features and Functions

“…Several [ 18 F]-labeled candidates have now been evaluated ( Patel et al, 2020 ), especially UCB-J derivatives including [ 18 F]MNI-1126 ( Constantinescu et al, 2019 ), also named [ 18 F]-SDM-8 and described by Li et al (2019a) and then referred as [ 18 F]-SynVesT-1 ( Li et al, 2021 ; Naganawa et al, 2021b ). Other recently developed compounds are [ 18 F]-SynVesT-2 ( Cai et al, 2020 ) and [ 18 F]-SDM-16 ( Zheng et al, 2021 ).…”

Acrolein, an endogenous aldehyde induces synaptic dysfunction in vitro and in vivo: Involvement of RhoA/ROCK2 pathway

“…Our results showed that acrolein significantly reduced the number of dendritic spines of cortical neurons after 4 weeks of administration, and the dendritic spines were swollen and dysplasia (Figure 2a ). Synapsin 1 and postsynaptic density 95 (PSD95) reflect the related functions of pre‐ and post‐synapses, respectively (Zhang, Wu, et al, 2021 ), while Synaptic Vesicle Glycoprotein 2A (SV2A) is a key protein that reflects the function of synaptic transmission (Zheng et al, 2021 ). The expression of these synapse‐related proteins in the hippocampus (PSD95: p < 0.05; SV2a and Synapsin1: p < 0.01) and cortex (SV2A: p < 0.05; PSD95 and Synapsin1: p < 0.01) of mice was significantly down‐regulated after administration of acrolein for 4 weeks (Figure 2b ).…”

PET Imaging of Synaptic Density: Challenges and Opportunities of Synaptic Vesicle Glycoprotein 2A PET in Small Animal Imaging

“…There are several 18 F-labeled SV2A tracers, i.e., [ 18 F]UCB-H ( Warnock et al, 2014 ), [ 18 F]UCB-J ( Li et al, 2019b ), [ 18 F]SynVesT-1 ( Li et al, 2019a , 2021 ), [ 18 F]SynVesT-2 ( Cai et al, 2020b ), and [ 18 F]SDM-16 ( Zheng et al, 2021 ), with different specific binding, brain kinetics, and peripheral metabolic rates. Figures 1A,B show the tracer kinetics in rhesus macaques and rats.…”

“…However, this is not likely to influence the quantitative analysis using this tracer, as [ 18 F]SynVesT-2 has rapid brain kinetics and only requires ∼30 min scanning time for reliable quantitative analysis based on our previous non-human primates’ results ( Cai et al, 2020b ). [ 18 F]SDM-16, a derivative of UCB-A ( Estrada et al, 2016 ) is the most metabolically stable SV2A PET tracer so far ( Zheng et al, 2021 ). Our evaluations of [ 18 F]SDM-16 in rodents are ongoing and the results will be reported in due course.…”