The purpose of this study is to longitudinally characterize and evaluate changes in synaptic density in the brain using novel positron-emission tomography (PET) scans; magnetic resonance imaging (MRI), and clinical laboratory markers associated with HIV-related injury in the central nervous system. This study will test hypotheses relating to the presence and mechanisms of aberrant brain structure at the synaptic level in living humans with virologically controlled HIV on antiretroviral therapy. To evaluate associations between PET imaging radiotracers [11C]UCB-J, a ligand for presynaptic vesicle protein 2A (SV2A), a vesicle membrane protein expressed in synapses, and PET [11C]PBR28 a measure of microglia function in the brain, the Yale PET center has developed an advanced approach of combining multiple distinct ligands in coordinated same-day PET imaging. Additionally, the study will evaluate the associations of this novel synaptic density marker with well-established clinical measures of neurocognitive performance and laboratory measures of blood and cerebrospinal fluid (CSF).

Start Date17 May 2023

Sponsor / Collaborator

Yale University

[+2]

NCT05465538 / RecruitingPhase 1/2IIT

Effect of Cannabis Use on Synaptic Density in Older Adults

The aim of the study is to examine the effect of cannabis use on brain synaptic density among older adults using [11C]UCB-J PET imaging.

Start Date06 Jul 2022

Sponsor / Collaborator

Yale University

[+1]

NCT05472818 / RecruitingEarly Phase 1IIT

SV2A Density Cannabis Use Disorder

The main purpose of this study is to determine whether hippocampal synaptic vesicle density estimated by hippocampal [11C]APP-311/[11C]UCB-J binding in individuals diagnosed with cannabis use disorder (CUDs) improves with at least 4 weeks of confirmed abstinence from cannabis, in comparison to healthy controls (HCs). Furthermore, any change in synaptic vesicle density will be placed in functional context by measuring verbal memory, which is sensitive to hippocampal function, before and after at least 4 weeks of confirmed abstinence. Finally, the relationship between hippocampal [11C]UCB-J binding in CUDs with measures of cannabis exposure (e.g., age of initiation, cumulative lifetime dose) will be explored.

Start Date01 May 2022

Sponsor / Collaborator

Yale University

[+1]

100 Clinical Results associated with 11C-UCB-J

100 Translational Medicine associated with 11C-UCB-J

100 Patents (Medical) associated with 11C-UCB-J

Literatures (Medical) associated with 11C-UCB-J

01 Sep 2024·Neuropharmacology

Excessive sucrose consumption reduces synaptic density and increases cannabinoid receptors in Göttingen minipigs

Article

Author: Bærentzen, Simone Larsen ; Thomsen, Majken Borup ; Brooks, David J ; Alstrup, Aage Ko ; Landau, Anne M ; Wegener, Gregers ; Winterdahl, Michael

Diets high in sucrose and fat are becoming more prevalent the world over, accompanied by a raised prevalence of cardiovascular diseases, cancers, diabetes, obesity, and metabolic syndrome. Clinical studies link unhealthy diets with the development of mental health disorders, particularly depression. Here, we investigate the effects of 12 days of sucrose consumption administered as 2 L of 25% sucrose solution daily for 12 days in Göttingen minipigs on the function of brain receptors involved in reward and motivation, regulating feeding, and pre- and post-synaptic mechanisms. Through quantitative autoradiography of cryostat sections containing limbic brain regions, we investigated the effects of sucrose restricted to a 1-h period each morning, on the specific binding of [³H]raclopride on dopamine D2/3 receptors, [³H]UCB-J at synaptic vesicle glycoprotein 2A (SV2A), [³H]MPEPγ at metabotropic glutamate receptor subtype 5 (mGluR5) and [³H]SR141716A at the cannabinoid receptor 1 (CB1). Compared to control diet animals, the sucrose group showed significantly lower [³H]UCB-J and [³H]MPEPγ binding in the prefrontal cortex. The sucrose-consuming minipigs showed higher hippocampal CB1 binding, but unaltered dopamine D2/3 binding compared to the control group. We found that the sucrose diet reduced the synaptic density marker while increasing CB1 binding in limbic brain structures, which may subserve maladaptive changes in appetite regulation and feeding. Further studies of the effects of diets and lifestyle habits on brain neuroreceptor and synaptic density markers are warranted.

15 May 2024·ACS Chemical Neuroscience

Exploring the Interactions between two Ligands, UCB-J and UCB-F, and Synaptic Vesicle Glycoprotein 2 Isoforms

Article

Author: Varrone, Andrea ; Zou, Rongfeng ; Li, Junhao ; Ågren, Hans ; Halldin, Christer ; Nag, Sangram

In silico modeling was applied to study the efficiency of two ligands, namely, UCB-J and UCB-F, to bind to isoforms of the synaptic vesicle glycoprotein 2 (SV2) that are involved in the regulation of synaptic function in the nerve terminals, with the ultimate goal to understand the selectivity of the interaction between UCB-J and UCB-F to different isoforms of SV2. Docking and large-scale molecular dynamics simulations were carried out to unravel various binding patterns, types of interactions, and binding free energies, covering hydrogen bonding and nonspecific hydrophobic interactions, water bridge, π-π, and cation-π interactions. The overall preference for bonding types of UCB-J and UCB-F with particular residues in the protein pockets can be disclosed in detail. A unique interaction fingerprint, namely, hydrogen bonding with additional cation-π interaction with the pyridine moiety of UCB-J, could be established as an explanation for its high selectivity over the SV2 isoform A (SV2A). Other molecular details, primarily referring to the presence of π-π interactions and hydrogen bonding, could also be analyzed as sources of selectivity of the UCB-F tracer for the three isoforms. The simulations provide atomic details to support future development of new selective tracers targeting synaptic vesicle glycoproteins and their associated diseases.

01 Apr 2024·Alzheimer's & Dementia

Tracing synaptic loss in Alzheimer's brain with SV2A PET‐tracer UCB‐J

Article

Author: Kumar, Amit ; Scarpa, Miriam ; Nordberg, Agneta

AbstractINTRODUCTIONSynaptic loss is an early prominent feature of Alzheimer's disease (AD). The recently developed novel synaptic vesicle 2A protein (SV2A) PET‐tracer UCB‐J has shown great promise in tracking synaptic loss in AD. However, there have been discrepancies between the findings and a lack of mechanistic insight.METHODSHere we report the first extensive pre‐clinical validation studies for UCB‐J in control (CN; n = 11) and AD (n = 11) brains using a multidimensional approach of post‐mortem brain imaging techniques, radioligand binding, and biochemical studies.RESULTS AND DISCUSSIONWe demonstrate that UCB‐J could target SV2A protein with high specificity and depict synaptic loss at synaptosome levels in AD brain regions compared to CNs. UCB‐J showed highest synaptic loss in AD hippocampus followed in descending order by frontal cortex, temporal cortex, parietal cortex, and cerebellum. 3H‐UCB‐J large brain‐section autoradiography and cellular/subcellular fractions binding studies indicated potential off‐target interaction with phosphorylated tau (p‐tau) species in AD brains, which could have subsequent clinical implications for imaging studies.Highlights

Synaptic positron emission tomography (PET)–tracer UCB‐J could target synaptic vesicle 2A protein (SV2A) with high specificity in Alzheimer's disease (AD) and control brains.

Synaptic PET‐tracer UCB‐J could depict synaptic loss at synaptosome levels in AD brain regions compared to control.

Potential off‐target interaction of UCB‐J with phosphorylated tau (p‐tau) species at cellular/subcellular levels could have subsequent clinical implications for imaging studies, warranting further investigations.

100 Deals associated with 11C-UCB-J

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Indication	Highest Phase	Country/Location	Organization	Date
Marijuana Abuse	Phase 2	US	National Institute on Drug Abuse	06 Jul 2022
Alzheimer Disease	Phase 1	-	UCB SA	-
Huntington Disease	Preclinical	BE	Alkermes Plc	14 Jan 2021

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