The Rise of Synaptic Density PET Imaging

Becker, Guillaume; Dammicco, Sylvestre; Bahri, Mohamed Ali; Salmon, Eric

doi:10.3390/molecules25102303

Cited by 26 publications

(22 citation statements)

References 58 publications

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“…Several SV2A PET tracers have been synthesized and evaluated in animals and human during the past few years by our group and others (Fig. 1) [7,15]. [ 18 F]UCB-H (2) [16][17][18] was the first SV2A PET tracer tested in human [17], followed by [ 11 C]UCB-J (3) [5], [ 11 C]UCB-A (1), [ 18 F]SynVesT-1(a.k.a.…”

Section: Introductionmentioning

confidence: 99%

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

Zheng¹,

Holden²,

Zheng³

et al. 2021

Eur J Nucl Med Mol Imaging

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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.

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Section: Introductionmentioning

confidence: 99%

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

Zheng¹,

Holden²,

Zheng³

et al. 2021

Eur J Nucl Med Mol Imaging

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“…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].…”

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confidence: 99%

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

et al. 2021

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Background Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [18F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we evaluate the reliability of the three most commonly used modelling approaches for [18F]UCB-H in the non-human cynomolgus primate, adding the coupled fit of the non-displaceable distribution volume (VND) as an alternative approach to improve unstable fit. The results are discussed in the light of the current state of SV2A PET ligands. Results [18F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), although the model did not always converge (large total volume of distribution (VT) or large uncertainty of the estimate). 2TCM with coupled fit K1/k2 across brain regions stabilized the quantification, and confirmed a lower specific signal of [18F]UCB-H compared to the newest SV2A-ligands. However, the measures of VND and the influx parameter (K1) are similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [19F]UCB-H, demonstrating only 50% displacement of the total [18F]UCB-H signal at maximal occupancy of SV2A. As previously demonstrated in clinical studies, the graphical method of Logan provided a more robust estimate of VT with only a small bias compared to 2TCM. Conclusions Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low.

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“…By extracting SV2A genomic data in clinical CRPC and NEPC specimens from the available gene expression repositories, we found that SV2A gene expression was significantly elevated. Given that several SV2A specific radiotracers (e.g., 11 C-UCB-A [ 46 ], 11 C-UCB-J [ 47 ], 18 F-UCB-H [ 48 ], and 18 F-SDM-8/SynVesT-1/2 [ 49 , 50 ]) have been reported for synaptic density PET imaging of neurodegenerative diseases [ 51 , 52 ], we performed a PET imaging evaluation in an NEPC xenograft model using 18 F-SynVesT-1, after having confirmed SV2A protein expression in NEPC cell lines and mouse xenografts through a comparative study.…”

Section: Introductionmentioning

confidence: 99%

Validation of SV2A-Targeted PET Imaging for Noninvasive Assessment of Neuroendocrine Differentiation in Prostate Cancer

Guan

Zhou

et al. 2021

IJMS

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Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal variant of prostate cancer (PCa), and it remains a diagnostic challenge. Herein we report our findings of using synaptic vesicle glycoprotein 2 isoform A (SV2A) as a promising marker for positron emission tomography (PET) imaging of neuroendocrine differentiation (NED). The bioinformatic analyses revealed an amplified SV2A gene expression in clinical samples of NEPC versus castration-resistant PCa with adenocarcinoma characteristics (CRPC-Adeno). Importantly, significantly upregulated SV2A protein levels were found in both NEPC cell lines and tumor tissues. PET imaging studies were carried out in NEPC xenograft models with 18F-SynVesT-1. Although 18F-SynVesT-1 is not a cancer imaging agent, it showed a significant uptake level in the SV2A+ tumor (NCI-H660: 0.70 ± 0.14 %ID/g at 50–60 min p.i.). The SV2A blockade resulted in a significant reduction of tumor uptake (0.25 ± 0.03 %ID/g, p = 0.025), indicating the desired SV2A imaging specificity. Moreover, the comparative PET imaging study showed that the DU145 tumors could be clearly visualized by 18F-SynVesT-1 but not 68Ga-PSMA-11 nor 68Ga-DOTATATE, further validating the role of SV2A-targeted imaging for noninvasive assessment of NED in PCa. In conclusion, we demonstrated that SV2A, highly expressed in NEPC, can serve as a promising target for noninvasive imaging evaluation of NED.

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The Rise of Synaptic Density PET Imaging

Cited by 26 publications

References 58 publications

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

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

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

Validation of SV2A-Targeted PET Imaging for Noninvasive Assessment of Neuroendocrine Differentiation in Prostate Cancer

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