Automated radiosynthesis of [<sup>11</sup>C]UCB‐J for imaging synaptic density by positron emission tomography

Sephton, Selena Milicevic; Miklovicz, Tünde; Russell, Joseph J.; Doke, Aniruddha K.; Li, Lei; Boros, István; Aigbirhio, Franklin I.

doi:10.1002/jlcr.3828

Cited by 14 publications

(20 citation statements)

References 15 publications

(38 reference statements)

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“…Participant recruitment and exclusion criteria are described in detail in the original publication49 . Here, we included data from the healthy volunteers (N=15, 8 females; age: 68 ± 7 years).The radioligand [ 11 C]UCB-J was synthesised at the Radiopharmacy Unit, Wolfson BrainImaging Centre, Cambridge University, using the methodology previously described24 . All participants underwent simultaneous 3T MRI and [ 11 C]UCB-J PET on a GE SIGNA PET/MR (GE Healthcare, Waukesha, USA).…”

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A synergistic core for human brain evolution and cognition

Mediano

et al. 2020

Preprint

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A fundamental question in neuroscience is how brain organisation gives rise to humans' unique cognitive abilities. Although complex cognition is widely assumed to rely on frontal and parietal brain regions, the underlying mechanisms remain elusive: current approaches are unable to disentangle different forms of information processing in the brain. Here, we introduce a powerful framework to identify synergistic and redundant contributions to neural information processing and cognition. Leveraging multimodal data including functional MRI, PET, cytoarchitectonics and genetics, we reveal that synergistic interactions are the fundamental drivers of complex human cognition. Whereas redundant information dominates sensorimotor areas, synergistic activity is closely associated with the brain's prefrontal-parietal and default networks; furthermore, meta-analytic results demonstrate a close relationship between high-level cognitive tasks and synergistic information. From an evolutionary perspective, the human brain exhibits higher prevalence of synergistic information than non-human primates. At the macroscale, we demonstrate that high-synergy regions underwent the highest degree of evolutionary cortical expansion. At the microscale, human-accelerated genes promote synergistic interactions by enhancing synaptic transmission. These convergent results provide critical insights that synergistic neural interactions underlie the evolution and functioning of humans' sophisticated cognitive abilities, and demonstrate the power of our widely applicable information decomposition framework.

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A synergistic core for human brain evolution and cognition

Mediano

et al. 2020

Preprint

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“…https://doi.org/10. 1101/2020 contributes to hyperexcitability of neurons and impaired calcium influx in transgenic mouse models (rTg4510) (Rocher et al, 2010).…”

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confidence: 99%

“…https://doi.org/10. 1101/2020 (B) Correlations between total PSP rating scale (PSPRS_total) and regional [ 11 C]UCB-J binding potential (BP ND ) in the frontal lobe and putamen for the two patient groups.…”

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confidence: 99%

“…https://doi.org/10. 1101/2020 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”

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confidence: 99%

“…We therefore tested whether PSP and CBD reduce synaptic plasticity in vivo, and in proportion to disease severity. We used positron emission tomography (PET) with the radioligand ((R)-1-((3-(methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), known as [ 11 C]UCB-J, manufactured at the Wolfson Brain Imaging Centre Radiopharmaceutical Unit (Milicevic Sephton et al, 2020). This ligand quantifies synaptic density (Finnema et al, 2016(Finnema et al, , 2017 based on its affinity for the presynaptic vesicle glycoprotein 2A (SV2a), that is ubiquitously expressed in brain synapses (Bajjalieh et al, 1993(Bajjalieh et al, , 1994.…”

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

Rokka

Nordeman

Roslin

et al. 2021

Labelled Comp Radiopharmac

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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.

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

Cited by 14 publications

References 15 publications

A synergistic core for human brain evolution and cognition

A synergistic core for human brain evolution and cognition

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

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

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

Cited by 14 publications

References 15 publications

A synergistic core for human brain evolution and cognition

A synergistic core for human brain evolution and cognition

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

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

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

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

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