Synaptic Imaging for Schizophrenia

Recruiting at 1 trial location

Overseen By Study Coordinator 2

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Davidzon, Guido, M.D.

Must be taking: Antipsychotics

Disqualifiers: Substance use, Neurological illness, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The purpose of this study is to utilize the radioactive positron emission tomography (PET) tracer \[11C\]UCB-J to test the neural synaptic pruning hypothesis of schizophrenia. This imaging method allows for the quantification of synaptic density in the living human brain and has the unprecedented ability to directly examine the synaptic pathology underlying neuropsychiatric disease. The neural synaptic pruning hypothesis posits that a key pathogenic process of schizophrenia is the over-exuberant elimination of neural synapses during development. The confirmation of reduced synaptic density in schizophrenia as evidenced by \[11C\]UCB-J has the potential to lead to a number of ground-breaking clinical innovations, such as laboratory-based diagnostics and prognostics, and novel, disease-modifying treatments.

Will I have to stop taking my current medications?

The trial requires that participants with schizophrenia be on a stable medication regimen for at least two weeks before testing, so you will not need to stop taking your current medications.

Is the [11C]UCB-J radiotracer safe for use in humans?

The [11C]UCB-J radiotracer has been used in human studies to measure synaptic density, and whole-body scans have been performed to determine its radiation dosimetry, which is a measure of the radiation dose absorbed by the body. This suggests that it has been evaluated for safety in terms of radiation exposure in humans. ^{1 2 3 4 5}

How does the drug 11C-UCB-J differ from other treatments for schizophrenia?

The drug 11C-UCB-J is unique because it uses PET imaging to measure synaptic vesicle density in the brain, which is a novel approach for understanding and potentially diagnosing schizophrenia. Unlike traditional treatments that focus on symptom management, this drug provides a way to visualize and quantify changes in synaptic density, offering insights into the underlying pathology of the condition. ^{1 2 3 4 5}

What evidence supports the effectiveness of the drug [11C]UCB-J for schizophrenia?

Research shows that people with schizophrenia have lower levels of synaptic density, which is linked to the severity of symptoms. The drug [11C]UCB-J is used in imaging to detect these lower levels, helping to understand and potentially track the progression of the disease. ^{3 4 6 7 8}

Who Is on the Research Team?

Jong H Yoon, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with a clinical diagnosis of schizophrenia, schizophreniform, or schizoaffective disorder. Participants must be on stable medication for at least two weeks and able to undergo a PET-MR scan without sedation.

Inclusion Criteria

I have been diagnosed with schizophrenia or a related disorder.

I can undergo a PET-MR scan without needing sedation.

My medication has not changed in the last two weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Imaging

Participants undergo positron emission tomography-magnetic resonance (PET-MR) imaging using the [11C]UCB-J radiotracer

120 minutes

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after imaging

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• [11C]UCB-J radiotracer

Trial Overview The study uses [11C]UCB-J radiotracer in a PET-MR imaging technique to measure synaptic density in the brain and test the neural synaptic pruning hypothesis related to schizophrenia.

How Is the Trial Designed?

Group I: Schizophrenia (SZ) Participants Experimental Treatment 2 Interventions

Participants will undergo positron emission tomography-magnetic resonance (PET-MR) imaging using the \[11C\]UCB-J radiotracer

Group II: Healthy Control (HC) Participants Experimental Treatment 2 Interventions

Participants will undergo positron emission tomography-magnetic resonance (PET-MR) imaging using the \[11C\]UCB-J radiotracer

Who Is Running the Clinical Trial?

Davidzon, Guido, M.D.

Lead Sponsor

Trials

3

Recruited

60+

Weston Havens Foundation

Collaborator

Trials

1

Recruited

60+

Published Research Related to This Trial

A comprehensive review of 18 meta-analyses involving over 50,000 subjects indicates that schizophrenia is linked to lower grey matter volumes, cortical thickness, and abnormal brain structure, suggesting significant synaptic alterations.

Key brain regions affected include the frontal, anterior cingulate, and temporal cortices, as well as the hippocampi, with evidence pointing towards lower synaptic density in these areas compared to healthy controls.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes. Howes, OD., Cummings, C., Chapman, GE., et al.[2023]

Patients with schizophrenia showed significantly lower synaptic vesicle density, as measured by the PET ligand [11C]UCB-J, across multiple brain regions compared to healthy controls, indicating a potential biomarker for the disease.

The study found that lower synaptic vesicle density in the frontal cortex was associated with more severe psychotic symptoms and poorer cognitive performance, suggesting a link between synaptic health and the severity of schizophrenia symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo evidence of lower synaptic vesicle density in schizophrenia. Radhakrishnan, R., Skosnik, PD., Ranganathan, M., et al.[2023]

In a study involving 18 patients with schizophrenia and 18 controls, researchers found significantly lower levels of synaptic vesicle glycoprotein 2A (SV2A) in the frontal and anterior cingulate cortices of patients, suggesting a link between synaptic dysfunction and schizophrenia symptoms.

The study also showed that antipsychotic medications did not significantly affect SV2A levels in rats, indicating that the observed lower levels in schizophrenia are not due to medication effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. Onwordi, EC., Halff, EF., Whitehurst, T., et al.[2023]

In a study involving 18 participants (9 with schizophrenia and 9 healthy controls), significant reductions in synaptic binding were observed in early-course schizophrenia patients, supporting the hypothesis of excess synaptic pruning as a key mechanism in the disease.

The findings showed widespread synaptic deficits in specific brain regions, correlating with cognitive performance and severity of delusions, indicating that these synaptic binding deficits are consistent and may be present even in the early stages of schizophrenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reductions in synaptic marker SV2A in early-course Schizophrenia. Yoon, JH., Zhang, Z., Mormino, E., et al.[2023]

In a study of 42 participants (21 with schizophrenia and 21 healthy volunteers), no significant differences in synaptic terminal density were found early in schizophrenia, suggesting that major changes in synaptic density may develop later in the illness.

However, subtle reductions in synaptic terminal density were observed in specific brain regions, such as the temporal lobe and anterior cingulate cortex, indicating that early synaptic changes may still occur in schizophrenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synaptic Terminal Density Early in the Course of Schizophrenia: An In Vivo UCB-J Positron Emission Tomographic Imaging Study of Synaptic Vesicle Glycoprotein 2A. Onwordi, EC., Whitehurst, T., Shatalina, E., et al.[2023]

The radioligand [11C]UCB-J selectively binds to synaptic vesicle glycoprotein 2A (SV2A) in mice, demonstrating its potential as a tool for measuring synaptic density in brain disorders.

The study confirmed that [11C]UCB-J has optimal kinetics for imaging, with a 60-minute scan duration being sufficient for reliable quantification, making it a promising method for investigating neuropsychiatric and neurodegenerative disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in mice. Bertoglio, D., Verhaeghe, J., Miranda, A., et al.[2021]

The newly developed PET radiotracer [18F]UCB-J, with a longer half-life of 110 minutes, shows promising pharmacokinetic properties and high brain uptake in nonhuman primates, making it a potential tool for studying synaptic abnormalities in neuropsychiatric disorders.

[18F]UCB-J demonstrated imaging characteristics similar to the previously developed [11C]UCB-J, indicating its effectiveness for in vivo imaging of synaptic vesicle glycoprotein 2A (SV2A) and potentially aiding in the diagnosis and understanding of conditions like epilepsy and Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and in vivo evaluation of [18F]UCB-J for PET imaging of synaptic vesicle glycoprotein 2A (SV2A). Li, S., Cai, Z., Zhang, W., et al.[2020]

The study assessed the radiation dosimetry of the radioligand 11C-UCB-J in four healthy adults, finding that it is safe for use in both adults and adolescents to measure synaptic density, which is important for understanding neuropsychiatric disorders.

The urinary bladder was identified as the dose-limiting organ for adult males, while the liver was the limit for adult females, and the large intestine for adolescents, indicating specific safety considerations for different demographics when using this imaging technique.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human adult and adolescent biodistribution and dosimetry of the synaptic vesicle glycoprotein 2A radioligand 11C-UCB-J. Bini, J., Holden, D., Fontaine, K., et al.[2023]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes. [2023]

2. England pubmed.ncbi.nlm.nih.gov

In vivo evidence of lower synaptic vesicle density in schizophrenia. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Reductions in synaptic marker SV2A in early-course Schizophrenia. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Synaptic Terminal Density Early in the Course of Schizophrenia: An In Vivo UCB-J Positron Emission Tomographic Imaging Study of Synaptic Vesicle Glycoprotein 2A. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in mice. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

Synthesis and in vivo evaluation of [18F]UCB-J for PET imaging of synaptic vesicle glycoprotein 2A (SV2A). [2020]

8. Germany pubmed.ncbi.nlm.nih.gov

Human adult and adolescent biodistribution and dosimetry of the synaptic vesicle glycoprotein 2A radioligand 11C-UCB-J. [2023]