Development and In Vivo Preclinical Imaging of Fluorine-18-Labeled Synaptic Vesicle Protein 2A (SV2A) PET Tracers

Constantinescu, Cristian; Tresse, Cédric; Zheng, Ming-Qiang; Gouasmat, Alexandra; Carroll, Vincent M.; Mistico, Laetitia; Alagille, David; Sandiego, Christine; Papin, Caroline; Marek, Kenneth; Seibyl, John; Tamagnan, Gilles; Barret, Olivier

doi:10.1007/s11307-018-1260-5

Cited by 63 publications

(69 citation statements)

References 27 publications

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“…Similar to data obtained in rodent and human (11,12), we observed in the NHP a good brain penetrance with ubiquitous brain uptake. Tissue in ux parameters of [18F]UCB-H were comparable to other SV2A radioligands for grey matter regions (13,24). In contrast to preliminary NHP data (23), but coherent with clinical data (12), a better goodness of t of the TACs was obtained with 2TCM compared to 1TCM, though not all TACs could be tted with 2TCM.…”

Section: Discussionsupporting

confidence: 51%

“…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-speci c ligands have been developed (9), [18F]UCB-H being one of the rst to be labelled (10), subsequently characterized in the rodent (10,11), and in the human brain (12). The demonstration of the co-localization of SV2A with other synaptic markers using [11C]-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 18F-labelled ligands (9,(14)(15)(16)(17)(18)(19). Preclinical characterization of [18F]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).…”

Section: Introductionmentioning

confidence: 99%

“…The demonstration of the co-localization of SV2A with other synaptic markers using [11C]-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 18F-labelled ligands (9,(14)(15)(16)(17)(18)(19). Preclinical characterization of [18F]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). In humans a preliminary study was performed on four healthy subjects (12), preceding a clinical study in Alzheimer's patients (25).…”

Section: Introductionmentioning

confidence: 99%

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The Pharmacokinetics of [18F]UCB-H Revisited in The Healthy Non-Human Primate Brain

Goutal

Guillermier

Becker

et al. 2020

Preprint

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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 aimed to characterize [18F]UCB-H in the non-human cynomolgus primate and to discuss the obtained results 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), even though a slow component led to instability for the estimation of k3 and k4, and hence the total volume of distribution. 2TCM with coupled fit K1/k2 across brain regions stabilized the quantification, and confirmed a lower non-displaceable binding potential, BPND (estimated by k3/k4), of [18F]UCB-H compared to the newest SV2A-ligands. However, the non-displaceable distribution volume (VND) and the influx parameter (K1) is 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. 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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Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Pharmacokinetics of [18F]UCB-H Revisited in The Healthy Non-Human Primate Brain

Goutal

Guillermier

Becker

et al. 2020

Preprint

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“…[11C]UCB-J is a high-affinity ligand for SV2A, and imaging with the tracer demonstrates approximately 40% lower SV2A-binding in the hippocampus among individuals with AD [78]. Fluorine-18-labeled SV2A PET compounds would facilitate broader use, and are currently in development and testing [79,80]. An example [11C]UCB-J PET scan acquired in a healthy control is shown in Figure 2D.…”

Section: Biomarkers For Synaptic Dysfunctionmentioning

confidence: 99%

Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies

2020

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Clinical trial results presented in 2019 suggest that antibody-based removal of cerebral amyloid β (Aβ) plaques may possibly clear tau tangles and modestly slow cognitive decline in symptomatic Alzheimer's disease (AD). Although regulatory approval of this approach is still pending, preparing the healthcare system for the advent of disease-modifying therapies against AD is imperative. In particular, it will be necessary to identify the most suitable biomarkers to facilitate appropriate treatment of AD. Here, we give an update on recent developments in fluid and imaging biomarkers for AD-related pathologies and discuss potential approaches which could be adopted to screen for and clarify the underlying pathology in people seeking medical advice because of cognitive symptoms. We succinctly review recent data regarding biomarkers for Aβ and tau pathology, neurodegeneration, synaptic dysfunction and inflammation, highlight the need for further research into common co-pathologies, and suggest how different biomarkers could be used (most likely in combination) to facilitate the development and clinical implementation of novel drug candidates against AD.

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“…Visualization of synapses in the living brain has recently been described through the labelling of synaptic vesicle glycoprotein 2A (SV2A) with the [ 11 C]UCB-J positron emission tomography (PET) ligand [111][112][113]. (Additional SV2A radioligands, [ 11 C]UCB-A and [ 18 F]UCB-H, have also been under development.)…”

Section: Biomarkers Of Synapse Damage or Lossmentioning

confidence: 99%

The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease

et al. 2020

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Background: Synapse damage and loss are fundamental to the pathophysiology of Alzheimer's disease (AD) and lead to reduced cognitive function. The goal of this review is to address the challenges of forging new clinical development approaches for AD therapeutics that can demonstrate reduction of synapse damage or loss. The key points of this review include the following: Synapse loss is a downstream effect of amyloidosis, tauopathy, inflammation, and other mechanisms occurring in AD. Synapse loss correlates most strongly with cognitive decline in AD because synaptic function underlies cognitive performance. Compounds that halt or reduce synapse damage or loss have a strong rationale as treatments of AD. Biomarkers that measure synapse degeneration or loss in patients will facilitate clinical development of such drugs. The ability of methods to sensitively measure synapse density in the brain of a living patient through synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations of synaptic proteins (e.g., neurogranin or synaptotagmin) in the cerebrospinal fluid (CSF), or functional imaging techniques such as quantitative electroencephalography (qEEG) provides a compelling case to use these types of measurements as biomarkers that quantify synapse damage or loss in clinical trials in AD. Conclusion: A number of emerging biomarkers are able to measure synapse injury and loss in the brain and may correlate with cognitive function in AD. These biomarkers hold promise both for use in diagnostics and in the measurement of therapeutic successes.

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Development and In Vivo Preclinical Imaging of Fluorine-18-Labeled Synaptic Vesicle Protein 2A (SV2A) PET Tracers

Abstract: We have identified a F-18-labeled tracer ([F]MNI-1126) that exhibits comparable in vivo characteristics and specificity for SV2A to [C]UCB-J in non-human primates, which makes [F]MNI-1126 a promising PET radiotracer for imaging SV2A in human trials.

Cited by 63 publications

References 27 publications

The Pharmacokinetics of [18F]UCB-H Revisited in The Healthy Non-Human Primate Brain

The Pharmacokinetics of [18F]UCB-H Revisited in The Healthy Non-Human Primate Brain

Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies

The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease

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