Acute transcutaneous auricular vagus nerve stimulation modulates presynaptic SV2A density in healthy rat brain: An in vivo microPET study.

Vagus nerve stimulation (VNS) is the subject of exploration as an adjunct treatment for neurological disorders such as epilepsy, chronic migraine, pain, and depression. A non-invasive form of VNS is transcutaneous auricular VNS (taVNS). Combining animal models and positron emission tomography (PET) may lead to a better understanding of the elusive mechanisms of taVNS. We evaluated the acute effect of electrical stimulation of the left vagus nerve via the ear on brain synaptic vesicle glycoprotein 2A (SV2A) as a measure of presynaptic density and glucose metabolism in naïve rats. Female Sprague-Dawley rats were imaged with [11C]UCB-J (n = 11) or [18F]fluorodeoxyglucose ([18F]FDG) PET (n = 13) on two separate days, (1) at baseline, and (2) after acute unilateral left taVNS or sham stimulation (30 min). We calculated the regional volume of distribution (VT) for [11C]UCB-J and standard uptake values (SUV) for [18F]FDG. We observed regional reductions of [11C]UCB-J binding in response to taVNS ranging from 36% to 59%. The changes in taVNS compared to baseline were significantly larger than those induced by sham stimulation. The differences were observed bilaterally in the frontal cortex, striatum, and midbrain. The [18F]FDG PET uptake remained unchanged following acute taVNS or sham stimulation compared to baseline values. This proof-of-concept study shows for the first time that acute taVNS for 30 min can modulate in vivo synaptic SV2A density in cortical and subcortical regions of healthy rats. Preclinical disease models and PET ligands of different targets can be a powerful combination to assess the therapeutic potential of taVNS.

Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [11 C]UCB-J Positron Emission Tomography Study.

BACKGROUND: Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits. OBJECTIVE: In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression. METHODS: Our cross-sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid-negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex- and age-matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [11 C]UCB-J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [11 C]UCB-J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty-two participants with PSP/CBD had a follow-up [11 C]UCB-J positron emission tomography scan after 1 year. We calculated the annualized change in [11 C]UCB-J nondisplaceable binding potential and correlated this with the change in clinical severity. RESULTS: We found significant annual synaptic loss within the frontal lobe (-3.5%, P = 0.03) and the right caudate (-3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination-Revised, R = -0.62, P = 0.003). CONCLUSIONS: We provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early-phase clinical trials of disease-modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [11 C]UCB-J and [18 F]FDG PET Study.

BACKGROUND: Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor. OBJECTIVE: The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease. METHOD: Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [18 F]fluorodeoxyglucose ([18 F]FDG) PET and [11 C]UCB-J, respectively. Volumes-of-interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios-1 values were obtained for 14 pre-selected brain regions. Between-group comparisons were conducted at voxel-level. RESULTS: We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non-demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel-wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density. CONCLUSION: Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [18 F]FDG PET and [11 C]UCB-J PET in Lewy body patients. The magnitude of reduced [18 F]FDG uptake was greater than the corresponding decline in [11 C]UCB-J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Longitudinal Imaging of Regional Brain Volumes, SV2A, and Glucose Metabolism In Huntington's Disease.

BACKGROUND: Development of disease-modifying treatments for Huntington's disease (HD) could be aided by the use of imaging biomarkers of disease progression. Positron emission tomography (PET) with 11 C-UCB-J, a radioligand for the brain-wide presynaptic marker synaptic vesicle protein 2A (SV2A), detects more widespread brain changes in early HD than volumetric magnetic resonance imaging (MRI) and 18 F-fludeoxyglucose (18 F-FDG) PET, but longitudinal 11 C-UCB-J PET data have not been reported. The aim of this study was to compare the sensitivity of 11 C-UCB-J PET, 18 F-FDG PET, and volumetric MRI for detection of longitudinal changes in early HD. METHODS: Seventeen HD mutation carriers (six premanifest and 11 early manifest) and 13 healthy controls underwent 11 C-UCB-J PET, 18 F-FDG PET, and volumetric MRI at baseline (BL) and after 21.4 ± 2.7 months (Y2). Within-group and between-group longitudinal clinical and imaging changes were assessed. RESULTS: The HD group showed significant 2-year worsening of Unified Huntington's Disease Rating Scale motor scores. There was significant longitudinal volume loss within the HD group in caudate (-4.5% ± 3.8%), putamen (-3.6% ± 3.5%), pallidum (-3.0% ± 2.7%), and frontal cortex (-2.0% ± 2.1%) (all P < 0.001). Within the HD group there was longitudinal loss of putaminal SV2A binding (6.4% ± 8.8%, P = 0.01) and putaminal glucose metabolism (-2.8% ± 4.4%, P = 0.008), but these changes were not significant after correction for multiple comparisons. Premanifest subjects at BL only had significantly lower SV2A binding than controls in basal ganglia structures, but at Y2 additionally had significant SV2A loss in frontal and parietal cortex, indicating spread of SV2A loss from subcortical to cortical regions. CONCLUSIONS: Volumetric MRI may be more sensitive than 11 C-UCB-J PET and 18 F-FDG PET for detection of 2-year brain changes in early HD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Identification of pre-synaptic density networks using [11C]UCB-J PET imaging and ICA in mice.

BACKGROUND: Synaptic vesicle glycoprotein 2A (SV2A) is a vesicle glycoprotein involved in neurotransmitter release. SV2A is located on the pre-synaptic terminals of neurons and visualized using the radioligand [11C]UCB-J and positron emission tomography (PET) imaging. Thus, SV2A PET imaging can provide a proxy for pre-synaptic density in health and disease. This study aims to apply independent component analysis (ICA) to SV2A PET data acquired in mice to identify pre-synaptic density networks (pSDNs), explore how ageing affects these pSDNs, and determine the impact of a neurological disorder on these networks. METHODS: We used [11C]UCB-J PET imaging data (n = 135) available at different ages (3, 7, 10, and 16 months) in wild-type (WT) C57BL/6J mice and in diseased mice (mouse model of Huntington's disease, HD) with reported synaptic deficits. First, ICA was performed on a healthy dataset after it was split into two equal-sized samples (n = 36 each) and the analysis was repeated 50 times in different partitions. We tested different model orders (8, 12, and 16) and identified the pSDNs. Next, we investigated the effect of age on the loading weights of the identified pSDNs. Additionally, the identified pSDNs were compared to those of diseased mice to assess the impact of disease on each pSDNs. RESULTS: Model order 12 resulted in the preferred choice to provide six reliable and reproducible independent components (ICs) as supported by the cluster-quality index (IQ) and regression coefficients (ß) values. Temporal analysis showed age-related statistically significant changes on the loading weights in four ICs. ICA in an HD model revealed a statistically significant disease-related effect on the loading weights in several pSDNs in line with the progression of the disease. CONCLUSION: This study validated the use of ICA on SV2A PET data acquired with [11C]UCB-J for the identification of cerebral pre-synaptic density networks in mice in a rigorous and reproducible manner. Furthermore, we showed that different pSDNs change with age and are affected in a disease condition. These findings highlight the potential value of ICA in understanding pre-synaptic density networks in the mouse brain.

Longitudinal Positron Emission Tomography Imaging of Presynaptic Terminals in Early Parkinson's Disease.

BACKGROUND: Imaging tools that allow quantification of Parkinson's disease (PD) progression could facilitate the development of disease-modifying therapies. Cross-sectional studies have shown presynaptic terminal damage in PD patients, but longitudinal data are limited. OBJECTIVES: The aim of this study was to longitudinally assess loss of presynaptic terminals in general and dopaminergic presynaptic terminals in particular as measures of disease progression in early PD. METHODS: A total of 27 patients with early PD and 18 age- and sex-matched healthy controls underwent positron emission tomography (PET) with 11 C-UCB-J, a ligand for the brain-wide presynaptic terminal marker SV2A, and with 18 F-FE-PE2I, a highly selective dopamine transporter ligand, in combination with a comprehensive motor and non-motor clinical assessment at baseline (BL) and after 26.5 ± 2.1 months (Y2). SUVR-1 images were calculated and volumes of interest were delineated based on individual 3D T1 magnetic resonance imaging (MRI). RESULTS: PD patients showed significant 2-year worsening of Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) (off medication) scores, but not of non-motor scores. Motor and non-motor scores in controls did not change significantly over 2 years. 18 F-FE-PE2I binding in caudate and putamen showed significant 2-year decline in the PD group and remained unchanged in controls. Longitudinal decline of striatal 18 F-FE-PE2I binding in PD did not correlate with longitudinal changes in MDS-UPDRS-III scores. 11 C-UCB-J PET did not show any region with significant 2-year change in PD or controls. CONCLUSIONS: 18 F-FE-PE2I PET showed robust 2-year decline in early PD, but 11 C-UCB-J PET did not. Longitudinal changes in 18 F-FE-PE2I binding did not correlate with clinical motor progression. © 2022 International Parkinson and Movement Disorder Society.

Synaptic density and cognitive performance in Alzheimer's disease: A PET imaging study with [11 C]UCB-J.

INTRODUCTION: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo. METHODS: We examined the relationship between synaptic density measured by [11 C]UCB-J PET and neuropsychological test performance in 45 participants with early AD. RESULTS: Global synaptic density showed a significant positive association with global cognition and performance on five individual cognitive domains in participants with early AD. Synaptic density was a stronger predictor of cognitive performance than gray matter volume. CONCLUSION: These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD.

Synaptic density in healthy human aging is not influenced by age or sex: a 11C-UCB-J PET study.

RATIONALE: 11C-UCB-J binds to synaptic vesicle glycoprotein 2A, a protein ubiquitously expressed in presynaptic nerve terminals, and can therefore serve as in vivo proxy of synaptic density. There are discrepancies in postmortem data on stability of synaptic density with healthy aging. In this study, healthy aging and sex as potential modifiers of 11C-UCB-J binding were investigated in healthy volunteers over 7 adult decades, assuming that the number of SV2A vesicles per synapse is not influenced by age or sex. METHODS: 80 healthy volunteers underwent 11C-UCB-J PET and structural T1 and T2 MR imaging. Grey matter changes with aging were firstly evaluated by voxel-based morphometry (VBM). Parametric 11C-UCB-J standardized uptake value ratio (SUVR) images were calculated using the centrum semiovale as reference tissue. To correct for atrophy-related partial volume effects, a region-based voxel-wise type partial volume correction (PVC) was applied in FreeSurfer. The correlations of 11C-UCB-J binding with age and with sex were investigated by a voxel-based and volume-of-interest (VOI)-based approach, and with and without PVC to assess the contribution of underlying morphology changes upon aging. RESULTS: Full results were available for 78 participants (19-85y; 33 M/45 F). VBM grey matter concentration changes with aging were most predominant in the perisylvian and frontal regions. After PVC, no significantly decreased 11C-UCB-J SUVR with aging was found in the voxel-based analysis, whereas the VOI-based analysis showed a slight decrease in the caudate nucleus (-1.7% decrease per decade, p= 0.0025) only. There was no association between sex and 11C-UCB-J SUVR, nor an interaction between aging and sex for this parameter. CONCLUSION: In vivo, PET using 11C-UCB-J does not support a cortical decrease of synaptic density with aging, whereas subcortically a small effect with aging in the caudate nucleus was observed. In addition, no association between synaptic density and sex was detected, which allows pooling of datasets of both sexes.

In vivo imaging of synaptic density with [11C]UCB-J PET in two mouse models of neurodegenerative disease.

The positron emission tomography (PET) radioligand [11C]UCB-J binds to synaptic vesicle protein 2A (SV2A) and is used to investigate synaptic density in the living brain. Clinical studies have indicated reduced [11C]UCB-J binding in Alzheimer's disease (AD) and Parkinson's disease (PD) brains compared to healthy controls. Still, it is unknown whether [11C]UCB-J PET can visualise synaptic loss in mouse models of these disorders. Such models are essential for understanding disease pathology and for evaluating the effects of novel disease-modifying drug candidates. In the present study, synaptic density in transgenic models of AD (ArcSwe) and PD (L61) was studied using [11C]UCB-J PET. Data were acquired during 60 min after injection, and time-activity curves (TACs) in different brain regions and the left ventricle of the heart were generated based on the dynamic PET images. The [11C]UCB-J brain concentrations were expressed as standardised uptake value (SUV) over time. The area under the SUV curve (AUC), the ratio of AUC in the brain to that in the heart (AUCbrain/blood), and the volume of distribution (VT) obtained by kinetic modelling using the heart TAC as input were compared between transgenic and age-matched wild type (WT) mice. The L61 mice displayed 11-13% lower AUCbrain/blood ratio and brain VT generated by kinetic modeling compared to the control WT mice. In general, also transgenic ArcSwe mice tended to show lower [11C]UCB-J brain exposure than age-matched WT controls, but variation within the different animal groups was high. Older WT mice (18-20 months) showed lower [11C]UCB-J brain exposure than younger WT mice (8-9 months). Together, these data imply that [11C]UCB-J PET reflects synaptic density in mouse models of neurodegeneration and that inter-subject variation is large. In addition, the study suggested that model-independent AUCbrain/blood ratio can be used to evaluate [11C]UCB-J binding as an alternative to full pharmacokinetic modelling.

Reduced Synaptic Density in Patients with Lewy Body Dementia: An [11 C]UCB-J PET Imaging Study.

BACKGROUND: Patients with Parkinson's disease (PD) often develop dementia, but the underlying substrate is incompletely understood. Generalized synaptic degeneration may contribute to dysfunction and cognitive decline in Lewy body dementias, but in vivo evidence is lacking. OBJECTIVE: The objective of this study was to assess the density of synapses in non-demented PD (nPD) subjects (N = 21), patients with PD-dementia or Dementia with Lewy bodies (DLB) (N = 13), and age-matched healthy controls (N = 15). METHOD: Using in vivo PET imaging and the novel synaptic-vesicle-glycoprotein 2A (SV2A) radioligand [11C]UCB-J, SUVR-1 values were obtained for 12 pre-defined regions. Volumes-of-interest were defined on MRI T1 scans. Voxel-level between-group comparisons of [11C]UCB-J SUVR-1 were performed. All subjects underwent neuropsychological assessment. Correlations between [11C]UCB- J PET and domain-specific cognitive functioning were examined. RESULTS: nPD patients only demonstrated significantly reduced SUVR-1 values in the substantia nigra (SN) compared to HC. DLB/PDD patients demonstrated reduced SUVR-1 values in SN and all cortical VOIs except for the hippocampus and amygdala. The voxel-based analysis supported the VOI results. Significant correlation was seen between middle frontal gyrus [11C]UCB-J SUVR-1 and performance on tests of executive function. CONCLUSION: Widespread cortical reduction of synaptic density was documented in a cohort of DLB/PDD subjects using in vivo [11C]UCB-J PET. Our study confirms previously reported synaptic loss in SN of nPD patients. [11C]UCB-J binding in selected cortical VOIs of the DLB/PDD patients correlated with their levels of cognitive function across relevant neuropsychological domains. These findings suggest that the loss of synaptic density contributes to cognitive impairment in nPD and DLB/PDD. © 2021 International Parkinson and Movement Disorder Society.

A comparative study on Suzuki-type 11 C-methylation of aromatic organoboranes performed in two reaction media.

The Suzuki-type cross coupling reaction is a palladium-mediated multistep reaction that has been used to synthesize several 11 C-labeled tracers for PET. However, the impact of the selected organoborane reagent and reaction medium on the radiochemical yield (RCY) has not been thoroughly investigated. To bridge this gap, we studied the synthesis of 1-[11 C]methylnaphthalene using four different organoborane precursors in reactions performed in DMF/water and THF/water. In the synthesis of 1-[11 C]methylnaphthalene, the best radiochemical yields (RCYs), approximately 50%, were obtained with boronic acid and pinacol ester precursors, whereas less than 4% RCY was obtained when performing the reaction with the N-methylimidodiacetic acid boronic ester (MIDA ester) precursor. 1-[11 C]methylnaphthalene was obtained in higher yields in almost all syntheses performed in THF/water as compared to DMF/water. This observation was in line with previously reported results for [11 C]UCB-J, a tracer for the synaptic vesicle glycoprotein 2A (SV2A) receptor, that also was obtained in higher RCY when synthesized in THF/water. The same trend was observed with [11 C]cetrozole, where the RCY was more than doubled in THF/water compared to the previously published synthesis performed in DMF. These results suggest that THF/water could be the preferred reaction medium when producing PET tracers via the Suzuki-type coupling reaction.

Loss of Presynaptic Terminal Integrity in the Substantia Nigra in Early Parkinson's Disease.

BACKGROUND: It has been hypothesized that the pathology of Parkinson's disease (PD) primarily affects presynaptic terminals and spreads trans-synaptically. OBJECTIVES: The main objective of this study was to assess the magnitude and anatomical extent of presynaptic terminal loss across the brain in early PD. A second objective was to compare loss of presynaptic terminals and cell bodies within the nigrostriatal tract. METHODS: A total of 30 patients with early PD and 20 age- and gender-matched healthy controls underwent positron emission tomography with 11 C-UCB-J, a ligand for the universal presynaptic terminal marker synaptic vesicle protein 2A (SV2A), and with the dopamine transporter ligand 18 F-FE-PE2I, as well as a detailed clinical assessment. Volumes of interest were delineated based on individual 3-dimensional T1 magnetic resonance imaging. BPND images were calculated. RESULTS: Patients with PD showed significant loss of SV2A binding in the substantia nigra only. Loss of dopamine transporter binding in the PD group was much greater in the putamen than in the substantia nigra. We found no correlations between SV2A or dopamine transporter binding and any of the clinical motor or nonmotor scores. Homologous voxel-based analysis in the PD group showed significant correlations between SV2A and dopamine transporter binding in the caudate and substantia nigra. CONCLUSIONS: Presynaptic terminals appear to be the most heavily affected subcellular compartment of nigrostriatal neurons in early PD. Moreover, early PD causes loss of presynaptic terminals that innervate the nigrostriatal neurons. This loss of presynaptic boutons in the substantia nigra may reflect an axonal response to target deprivation or could possibly point to a trans-synaptic mode of propagation of the disease process. © 2020 International Parkinson and Movement Disorder Society.

Synaptic Loss in Primary Tauopathies Revealed by [11 C]UCB-J Positron Emission Tomography.

BACKGROUND: Synaptic loss is a prominent and early feature of many neurodegenerative diseases. OBJECTIVES: We tested the hypothesis that synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) (Richardson's syndrome) and amyloid-negative corticobasal syndrome (CBS). METHODS: Forty-four participants (15 CBS, 14 PSP, and 15 age-/sex-/education-matched controls) underwent PET with the radioligand [11 C]UCB-J, which binds to synaptic vesicle glycoprotein 2A, a marker of synaptic density; participants also had 3 Tesla MRI and clinical and neuropsychological assessment. RESULTS: Nine CBS patients had negative amyloid biomarkers determined by [11 C]PiB PET and hence were deemed likely to have corticobasal degeneration (CBD). Patients with PSP-Richardson's syndrome and amyloid-negative CBS were impaired in executive, memory, and visuospatial tasks. [11 C]UCB-J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala, and subcortical structures in both PSP and CBD patients compared to controls (P < 0.01), with median reductions up to 50%, consistent with postmortem data. Reductions of 20% to 30% were widespread even in areas of the brain with minimal atrophy. There was a negative correlation between global [11 C]UCB-J binding and the PSP and CBD rating scales (R = -0.61, P < 0.002; R = -0.72, P < 0.001, respectively) and a positive correlation with the revised Addenbrooke's Cognitive Examination (R = 0.52; P = 0.01). CONCLUSIONS: We confirm severe synaptic loss in PSP and CBD in proportion to disease severity, providing critical insight into the pathophysiology of primary degenerative tauopathies. [11 C]UCB-J may facilitate treatment strategies for disease-modification, synaptic maintenance, or restoration. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Autoradiographic mapping of synaptic vesicle glycoprotein 2A in non-human primate and human brain.

Synaptic vesicle glycoprotein 2A (SV2A) has been previously characterized as an imaging biomarker for assessment of synaptic density in positron emission tomography (PET) studies of patients with neurological conditions. To provide detailed maps of the brain localization of SV2A autoradiography studies were carried out using the SV2A radioligand [11 C]UCB-J and whole hemisphere sections of non-human primate (NHP) and human brain. Binding of [11 C]UCB-J was observed in all evaluated grey matter structures of the primate brain, with highest density in the caudate nucleus and cortex and lowest density in pons and globus pallidus. The density of [11 C]UCB-J binding sites in human brain showed a good correlation with that in NHP brain. Binding of [11 C]UCB-J in the white matter was very low relative to that in grey matter containing structures and was only inhibited to a minor extent by co-incubation with a saturating concentration of unlabelled UCB-J. The high-resolution images obtained in the present study may aid the interpretation of data acquired in human subjects examined using [11 C]UCB-J in PET studies. In addition, observation of low binding for [11 C]UCB-J in white matter (centrum semiovale) supports that this structure can be used as a reference region for quantitative analysis of [11 C]UCB-J PET data.

Automated radiosynthesis of [11 C]UCB-J for imaging synaptic density by positron emission tomography.

An automated radiosynthesis of carbon-11 positron emission tomography radiotracer [11 C]UCB-J for imaging the synaptic density biomarker synaptic vesicle glycoprotein SV2A was established using Synthra RNPlus synthesizer. Commercially available trifluoroborate UCB-J analogue was used as a radiolabelling precursor, and the desired radiolabelled product was isolated in 11 ± 2% (n = 7) nondecay corrected radiochemical yield and formulated as a 10% EtOH solution in saline with molar activities of 20 to 100 GBq/µmol. The method was based upon the palladium(0)-mediated Suzuki cross-coupling reaction and [11 C]CH3 I as a radiolabelling synthon. The isolated product was cGMP compliant as demonstrated by the results of quality control analysis.

In vivo measurement of widespread synaptic loss in Alzheimer's disease with SV2A PET.

INTRODUCTION: Synaptic loss is a robust and consistent pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising biomarker of synaptic density. METHODS: We measured SV2A binding in 34 participants with early AD and 19 cognitively normal (CN) participants using [11 C]UCB-J PET and a cerebellar reference region for calculation of the distribution volume ratio. RESULTS: We observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume. CONCLUSION: We were able to measure widespread synaptic loss due to AD using [11 C]UCB-J PET. Future studies will continue to evaluate the utility of SV2A PET for tracking AD progression and for monitoring potential therapies.

Quantifying SV2A density and drug occupancy in the human brain using [11C]UCB-J PET imaging and subcortical white matter as reference tissue.

PURPOSE: A [11C]UCB-J blocking study was performed in healthy volunteers to validate simplified, non-invasive measures for quantifying presynaptic SV2A expression using subcortical white matter as reference tissue. METHODS: Ninety minutes dynamic [11C]UCB-J PET scanning with arterial blood sampling was performed in 10 healthy volunteers (8 M/2F; age 27.6 ± 10.0 yrs), before and after administration of a novel chemical entity with selective affinity for SV2A. The centrum semi-ovale (SO) was validated as reference region by comparing baseline and post treatment distribution volume (VT). Using SO as reference tissue, Binding Potential (BPSO) using a Simplified Reference Tissue Model (SRTM, down to 60 min acquisition) and Standardized Uptake Value Ratios (60-90 min post injection - SUVRSO,60-90min) were compared with regional distribution volume ratios (DVR). Next, SV2A occupancy values based on SRTM BPSO and SUVRSO,60-90min were compared to occupancy estimates using regional VT values and a Lassen plot. RESULTS: After pretreatment, regional VT values were reduced significantly except for SO. Highly significant correlations were found between DVR, SRTM BPSO and SUVRSO,60-90min. Compared to DVR, baseline SRTM BPSO showed a small bias (≤ 6.1%) with lower precision for shorter acquisition times, while SUVRSO,60-90min showed 3.5% bias with similar precision. Differences between SV2A occupancy values based on SUVRSO,60-90min and occupancy estimates using VT and a Lassen plot were small but significant, while negligible bias was found for SRTM based occupancy estimates (at least 70 min acquisition). CONCLUSION: This [11C]UCB-J blocking study validated SO as a suitable reference region for non-invasive quantification of SV2A availability and drug occupancy in the human brain. Accurate quantification can be achieved by using either SUVRSO,60-90min with a 60-90 min PET acquisition or SRTM BPSOwith at least 70 min dynamic PET acquisition.

A single-center, open-label positron emission tomography study to evaluate brivaracetam and levetiracetam synaptic vesicle glycoprotein 2A binding in healthy volunteers.

OBJECTIVE: Brivaracetam (BRV) and levetiracetam (LEV) are antiepileptic drugs that bind synaptic vesicle glycoprotein 2A (SV2A). In vitro and in vivo animal studies suggest faster brain penetration and SV2A occupancy (SO) after dosing with BRV than LEV. We evaluated human brain penetration and SO time course of BRV and LEV at therapeutically relevant doses using the SV2A positron emission tomography (PET) tracer 11 C-UCB-J (EP0074; NCT02602860). METHODS: Healthy volunteers were recruited into three cohorts. Cohort 1 (n = 4) was examined with PET at baseline and during displacement after intravenous BRV (100 mg) or LEV (1500 mg). Cohort 2 (n = 5) was studied during displacement and 4 hours postdose (BRV 50-200 mg or LEV 1500 mg). Cohort 3 (n = 4) was examined at baseline and steady state after 4 days of twice-daily oral dosing of BRV (50-100 mg) and 4 hours postdose of LEV (250-600 mg). Half-time of 11 C-UCB-J signal change was computed from displacement measurements. Half-saturation concentrations (IC50 ) were determined from calculated SO. RESULTS: Observed tracer displacement half-times were 18 ± 6 minutes for BRV (100 mg, n = 4), 9.7 and 10.1 minutes for BRV (200 mg, n = 2), and 28 ± 6 minutes for LEV (1500 mg, n = 6). Estimated corrected half-times were 8 minutes shorter. The SO was 66%-70% for 100 mg intravenous BRV, 84%-85% for 200 mg intravenous BRV, and 78%-84% for intravenous 1500 mg LEV. The IC50 of BRV (0.46 µg/mL) was 8.7-fold lower than of LEV (4.02 µg/mL). BRV data fitted a single SO versus plasma concentration relationship. Steady state SO for 100 mg BRV was 86%-87% (peak) and 76%-82% (trough). SIGNIFICANCE: BRV achieves high SO more rapidly than LEV when intravenously administered at therapeutic doses. Thus, BRV may have utility in treating acute seizures; further clinical studies are needed for confirmation.

Validation of a Simplified Tissue-to-Reference Ratio Measurement Using SUVR to Assess Synaptic Density Alterations in Alzheimer Disease with [11C]UCB-J PET.

Simplified methods of acquisition and quantification would facilitate the use of synaptic density imaging in multicenter and longitudinal studies of Alzheimer disease (AD). We validated a simplified tissue-to-reference ratio method using SUV ratios (SUVRs) for estimating synaptic density with [11C]UCB-J PET. Methods: Participants included 31 older adults with AD and 16 with normal cognition. The distribution volume ratio (DVR) using simplified reference tissue model 2 was compared with SUVR at short scan windows using a whole-cerebellum reference region. Results: Synaptic density was reduced in AD participants using DVR or SUVR. SUVR using later scan windows (60-90 or 70-90 min) was minimally biased, with the strongest correlation with DVR. Effect sizes using SUVR at these late time windows were minimally reduced compared with effect sizes with DVR. Conclusion: A simplified tissue-to-reference method may be useful for multicenter and longitudinal studies seeking to measure synaptic density in AD.

SV2A PET imaging in human neurodegenerative diseases.

This manuscript presents a thorough review of synaptic vesicle glycoprotein 2A (SV2A) as a biomarker for synaptic integrity using Positron Emission Tomography (PET) in neurodegenerative diseases. Synaptic pathology, characterized by synaptic loss, has been linked to various brain diseases. Therefore, there is a need for a minimally invasive approach to measuring synaptic density in living human patients. Several radiotracers targeting synaptic vesicle protein 2A (SV2A) have been created and effectively adapted for use in human subjects through PET scans. SV2A is an integral glycoprotein found in the membranes of synaptic vesicles in all synaptic terminals and is widely distributed throughout the brain. The review delves into the development of SV2A-specific PET radiotracers, highlighting their advancements and limitations in neurodegenerative diseases. Among these tracers, 11C-UCB-J is the most used so far. We summarize and discuss an increasing body of research that compares measurements of synaptic density using SV2A PET with other established indicators of neurodegenerative diseases, including cognitive performance and radiological findings, thus providing a comprehensive analysis of SV2A's effectiveness and reliability as a diagnostic tool in contrast to traditional markers. Although the literature overall suggests the promise of SV2A as a diagnostic and therapeutic monitoring tool, uncertainties persist regarding the superiority of SV2A as a biomarker compared to other available markers. The review also underscores the paucity of studies characterizing SV2A distribution and loss in human brain tissue from patients with neurodegenerative diseases, emphasizing the need to generate quantitative neuropathological maps of SV2A density in cases with neurodegenerative diseases to fully harness the potential of SV2A PET imaging in clinical settings. We conclude by outlining future research directions, stressing the importance of integrating SV2A PET imaging with other biomarkers and clinical assessments and the need for longitudinal studies to track SV2A changes throughout neurodegenerative disease progression, which could lead to breakthroughs in early diagnosis and the evaluation of new treatments.