[11C]UCB-A, a novel PET tracer for synaptic vesicle protein 2A

Estrada, Sergio; Lubberink, Mark; Thibblin, Alf; Sprycha, Margareta; Buchanan, Tim; Mestdagh, Nathalie; Kenda, Benoît; Mercier, Joël; Provins, Laurent; Gillard, Michel; Tytgat, Dominique; Antoni, Gunnar

doi:10.1016/j.nucmedbio.2016.03.004

Cited by 52 publications

(74 citation statements)

References 25 publications

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“…12,14 Both radiotracers have shown specific binding to SV2A; however, [ 11 C]UCB-A was limited by its slow kinetics and metabolism in both rats and pigs. 12 On the other hand, [ 18 F]UCB-H had good kinetics, but direct comparison with [ 11 C]UCB-J in nonhuman primates suggested the latter has higher specific binding. 11 Consistently, Warnock et al 38 reported a decrease of approximately 44% in the whole-brain [ 18 F]UCB-H binding in rats pretreated with 100 mg/kg of LEV, while in the present study, with a 50 mg/kg dose in mice, we could observe a decrease of 78% of the [ 11 C]UCB-J binding to SV2A.…”

Section: Discussionmentioning

confidence: 99%

Validation and noninvasive kinetic modeling of [¹¹C]UCB-J PET imaging in mice

Bertoglio

Verhaeghe

Miranda

et al. 2019

J Cereb Blood Flow Metab

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Synaptic pathology is associated with several brain disorders, thus positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) using the radioligand [11C]UCB-J may provide a tool to measure synaptic alterations. Given the pivotal role of mouse models in understanding neuropsychiatric and neurodegenerative disorders, this study aims to validate and characterize [11C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examined kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metabolism. Regional TACs during baseline showed rapid uptake of [11C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. VT (IDIF) values estimated with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, p < 0.0001), with 1TCM performing better than 2TCM for K1 (IDIF). A scan duration of 60 min was sufficient for reliable VT (IDIF) and K1 (IDIF) estimations. In vivo metabolism of [11C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [11C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic density in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.

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Section: Discussionmentioning

confidence: 99%

Validation and noninvasive kinetic modeling of [¹¹C]UCB-J PET imaging in mice

Bertoglio

Verhaeghe

Miranda

et al. 2019

J Cereb Blood Flow Metab

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“…Among all the synaptic vesicle proteins, only synaptic vesicle protein 2A (SV2A) 155 has brain penetrant small molecule ligands as leading compounds for tracer development 156,157 . In the past several years, a series of SV2A PET imaging probes have been developed and evaluated in rodents, nonhuman primates (Fig 3), and humans 158‐164 . Among the PET tracers evaluated in human studies, [ 11 C]UCB‐J and [ 18 F]SDM‐8 are the most promising ones, giving reliable quantitative information on the synapse densities of different brain regions, and additional tracers with more favorable properties are in development 165 .…”

Section: Cell Body and Synapse Pathologymentioning

confidence: 99%

Imaging Mechanisms of Disease Progression in Multiple Sclerosis: Beyond Brain Atrophy

Bagnato

Gauthier

Laule

et al. 2020

Journal of Neuroimaging

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Clinicians involved with different aspects of the care of persons with multiple sclerosis (MS) and scientists with expertise on clinical and imaging techniques convened in Dallas, TX, USA on February 27, 2019 at a North American Imaging in MultipleSclerosis Cooperative workshop meeting. The aim of the workshop was to discuss cardinal pathobiological mechanisms implicated in the progression of MS and novel imaging techniques, beyond brain atrophy, to unravel these pathologies. Indeed, although brain volume assessment demonstrates changes linked to disease progression, identifying the biological mechanisms leading up to that volume loss are key for understanding disease mechanisms. To this end, the workshop focused on the application of advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging techniques to assess and measure disease progression in both the brain and the spinal cord. Clinical translation of quantitative MRI was recognized as of vital importance, although the need to maintain a relatively short acquisition time mandated by most radiology departments remains the major obstacle toward this effort. Regarding PET, the panel agreed upon its utility to identify ongoing pathological processes. However, due to costs, required expertise, and the use of ionizing radiation, PET was not considered to be a viable option for ongoing care of persons with MS. Collaborative efforts fostering robust study designs and imaging technique standardization across scanners and centers are needed to unravel disease mechanisms leading to progression and discovering medications halting neurodegeneration and/or promoting repair.

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“…Other PET tracers based on 11 C-labeling have been also recently developed in preclinical species, e.g. [ 11 C]UCB-A [77] and [ 11 C]UCB-J [78]. As with UCB-H, UCB-J [( R )-1-((3-(methyl- 11 C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one] is a heterocyclic non-acetamide compound [74].…”

Section: The Role Of Sv2a In Modulating Neuronal Excitability In the mentioning

confidence: 99%

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

Löscher¹,

et al. 2016

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The synaptic vesicle glycoprotein SV2A belongs to the major facilitator superfamily (MFS) of transporters and is an integral constituent of synaptic vesicle membranes. SV2A has been demonstrated to be involved in vesicle trafficking and exocytosis, processes crucial for neurotransmission. The anti-seizure drug levetiracetam was the first ligand to target SV2A and displays a broad spectrum of anti-seizure activity in various preclinical models. Several lines of preclinical and clinical evidence, including genetics and protein expression changes, support an important role of SV2A in epilepsy pathophysiology. While the functional consequences of SV2A ligand binding are not fully elucidated, studies suggest that subsequent SV2A conformational changes may contribute to seizure protection. Conversely, the recently discovered negative SV2A modulators, such as UCB0255, counteract the anti-seizure effect of levetiracetam and display procognitive properties in preclinical models. More broadly, dysfunction of SV2A may also be involved in Alzheimer’s disease and other types of cognitive impairment, suggesting potential novel therapies for levetiracetam and its congeners. Furthermore, emerging data indicate that there may be important roles for two other SV2 isoforms (SV2B and SV2C) in the pathogenesis of epilepsy, as well as other neurodegenerative diseases. Utilization of recently developed SV2A positron emission tomography ligands will strengthen and reinforce the pharmacological evidence that SV2A is a druggable target, and will provide a better understanding of its role in epilepsy and other neurological diseases, aiding in further defining the full therapeutic potential of SV2A modulation.

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[11C]UCB-A, a novel PET tracer for synaptic vesicle protein 2A

Cited by 52 publications

References 25 publications

Validation and noninvasive kinetic modeling of [¹¹C]UCB-J PET imaging in mice

Validation and noninvasive kinetic modeling of [¹¹C]UCB-J PET imaging in mice

Imaging Mechanisms of Disease Progression in Multiple Sclerosis: Beyond Brain Atrophy

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

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[11C]UCB-A, a novel PET tracer for synaptic vesicle protein 2A

Cited by 52 publications

References 25 publications

Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in mice

Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in mice

Imaging Mechanisms of Disease Progression in Multiple Sclerosis: Beyond Brain Atrophy

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

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Product

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Validation and noninvasive kinetic modeling of [¹¹C]UCB-J PET imaging in mice

Validation and noninvasive kinetic modeling of [¹¹C]UCB-J PET imaging in mice