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

Koole, Michel; Aalst, June van; Devrome, Martijn; Mertens, Nathalie; Serdons, Kim; Lacroix, Benoı̂t; Mercier, Joël; Sciberras, David; Maguire, R. Paul; Laere, Koen Van

doi:10.1007/s00259-018-4119-8

Cited by 81 publications

(94 citation statements)

References 23 publications

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“…Although no known reference region exists for 18 F-BCPP-EF, we found that V T estimates were about 50% lower in the centrum semiovale than in gray matter regions. 11 C-UCB-J V T estimates were about 60% lower in the centrum semiovale than in gray matter regions, supporting previous suggestions of its potential use as a reference region for 11 C-UCB-J (33). Blocking studies with specific MC1 and SV2A compounds should be conducted in both healthy and disease cohorts to confirm the viability of the centrum semiovale as a reference region.…”

Section: Discussionsupporting

confidence: 77%

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: ¹⁸F-BCPP-EF, ¹¹C-SA-4503, and ¹¹C-UCB-J

et al. 2019

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Mitochondrial complex 1 is involved in maintaining brain bioenergetics; σ-1 receptor responds to neuronal stress; and synaptic vesicle protein 2A reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here, we characterize the kinetic behavior of 3 PET radioligands-18 F-BCPP-EF, 11 C-SA-4503, and 11 C-UCB-J-for the measurement of mitochondrial complex 1, σ-1 receptor, and synaptic vesicle protein 2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases. Methods: Twelve human subjects underwent dynamic PET scans with each radioligand, including associated arterial blood sampling. A range of kinetic models was investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. Results: All 3 radioligands readily entered the brain and yielded heterogeneous uptake consistent with the known distribution of the targets. The optimal models determined for the regional estimates of volume of distribution were multilinear analysis 1 (MA1) and the 2-tissue-compartment model for 18 F-BCPP-EF, MA1 for 11 C-SA-4503, and both MA1 and the 1-tissue-compartment model for 11 C-UCB-J. Acquisition times of 70, 80, and 60 min for 18 F-BCPP-EF, 11 C-SA-4503, 11 C-UCB-J, respectively, provided good estimates of regional volume of distribution values. An effect of age was observed on 18 F-BCPP-EF and 11 C-UCB-J signal in the caudate. Conclusion: These ligands can be assessed for their potential to stratify patients or monitor the progression of molecular neuropathology in neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 77%

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: ¹⁸F-BCPP-EF, ¹¹C-SA-4503, and ¹¹C-UCB-J

et al. 2019

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“…In Cohorts 2 and 3, V T values were computed using the 1TC model to fit regional time‐activity curves . The V T estimate was derived from the model fit parameters, K 1 and k 2 .…”

Section: Methodsmentioning

confidence: 99%

“…In Cohorts 2 and 3, V T values were computed using the 1TC model to fit regional time-activity curves. 21,22 The V T estimate was derived from the model fit parameters, K 1 and k 2 . Regional V T values were computed for 23 regions, including amygdala, anterior cingulum, anterior insula, caudate nucleus, cerebellum, dorsolateral prefrontal cortex, frontal cortex, fusiform, globus pallidus, hippocampus, insula, occipital cortex, orbitofrontal cortex, parahippocampal gyrus, parietal cortex, posterior cingulum, posterior insula, putamen, substantia nigra, temporal cortex, thalamus, ventromedial prefrontal cortex, and ventral striatum.…”

Section: Quantitative Analysismentioning

confidence: 99%

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

et al. 2019

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Summary 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 11C‐UCB‐J (; ). 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 11C‐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.

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“…Regional time-activity curves were extracted with and without correction for cerebrospinal fluid (CSF) partial volume using the SPM12 CSF probability map, again smoothed to PET resolution. To quantify SV2A density, [ 11 C]UCB-J non-displaceable binding potential (BP ND ) was determined using a basis function implementation of the simplified reference tissue model (Wu and Carson, 2002), with the reference tissue defined in the centrum semiovale (Koole et al, 2019;Rossano et al, 2019). Group average BP ND images (illustrated in Fig1 A-C) were obtained by spatially normalizing individual T1weighted MRI (and thereby co-registered BP ND map) to MNI space, and then to the group template using ANTS.…”

Section: Neuroimagingmentioning

confidence: 99%

Synaptic loss in primary tauopathies revealed by [₁₁C]UCB-J positron emission tomography

Holland

Jones

Savulich

et al. 2020

Preprint

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Synaptic loss is prominent in several human neurodegenerative diseases. We tested the hypothesis that synaptic density is reduced by the primary tauopathies of progressive supranuclear palsy (PSP-Richardson's syndrome) and corticobasal syndrome (CBS). Thirtyseven participants (12 CBS, 10 PSP, and 15 age-/sex-/education-matched controls) underwent clinical and neuropsychological assessment, 3T magnetic resonance imaging, and positron emission tomography with the radioligand [ 11 C]UCB-J which targets the Synaptic Vesicle Glycoprotein 2A (SV2A). 10 CBS patients had negative β -amyloid biomarkers (Pittsburgh Compound B PET). As expected, patients with PSP-Richardson's syndrome and amyloidnegative 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 CBS patients compared to controls (p<0.001), with reductions up to 50%, consistent with post mortem data. The revised Addenbrooke's Cognitive Examination score correlated positively with [ 11 C]UCB-J binding in frontal, temporal, parietal, occipital, and cingulate cortices, as well as in the hippocampus, insula and amygdala, p<0.05); putamen and frontal lobe [ 11 C]UCB-J binding correlated inversely with the PSP rating scale ( p<0.05). In conclusion, we confirm severe synaptic loss in PSP and CBS, which correlates with disease severity, providing critical insights into the underlying pathophysiology of primary degenerative tauopathies and supporting potential treatment strategies based on synaptic maintenance or restoration. Keywords: Synaptic Vesicle Protein 2A, UCB-J, PET, tauopathy, PSP. Abbreviations: [ 11 C]UCBJ = (R)-1-((3-(methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5trifluorophenyl)pyr-rolidin-2-one); BP ND = non-displaceable binding potential; PSP = Progressive Supranuclear Palsy, CBS = corticobasal syndrome, CBD = Corticobasal Degeneration; [ 11 C]PiB = (methyl-11C) Pittsburgh compound B; UPDRS = Unified Parkinson's Disease Rating Scale; PSPRS = Progressive Supranuclear Gaze Palsy Rating Scale; ACE-R = Addenbrooke's Cognitive Examination -Revised; MMSE = Mini-mental State Examination; CDR = Clinical Dementia Rating Scale; CBI = Cambridge Behavioural Inventory -Revised; SEADL = Schwab and England Activities of Daily Living Scale. ns = non-significant at p<0.05.

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

Cited by 81 publications

References 23 publications

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: ¹⁸F-BCPP-EF, ¹¹C-SA-4503, and ¹¹C-UCB-J

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: ¹⁸F-BCPP-EF, ¹¹C-SA-4503, and ¹¹C-UCB-J

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

Synaptic loss in primary tauopathies revealed by [₁₁C]UCB-J positron emission tomography

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

Cited by 81 publications

References 23 publications

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: 18F-BCPP-EF, 11C-SA-4503, and 11C-UCB-J

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: 18F-BCPP-EF, 11C-SA-4503, and 11C-UCB-J

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

Synaptic loss in primary tauopathies revealed by [11C]UCB-J positron emission tomography

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Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: ¹⁸F-BCPP-EF, ¹¹C-SA-4503, and ¹¹C-UCB-J

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: ¹⁸F-BCPP-EF, ¹¹C-SA-4503, and ¹¹C-UCB-J

Synaptic loss in primary tauopathies revealed by [₁₁C]UCB-J positron emission tomography