EAAT2 PET Tracer for Dementia

Overseen By David Wilson, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: David Wilson

Must not be taking: CNS drugs, Nicotine cessation

Disqualifiers: Pregnancy, Breast-feeding, Claustrophobia, others

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

Compensation: Varies

Number of Visits: Unknown

102 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new PET scan agent called [18F]RP-115, which may detect early brain changes in individuals with Alzheimer's disease (AD) or frontotemporal dementia (FTD). Researchers aim to determine its safety and effectiveness by comparing patients with AD, FTD, and healthy individuals. Those with AD or FTD, along with a study partner familiar with them, might be suitable for this trial. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

Yes, you must stop taking any central nervous system (CNS) prescription drugs for three weeks before participating in the trial.

What prior data suggests that this PET agent is safe for humans?

Research has shown that injections of \[18F\]RP-115 are safe for people. Studies have found that the kidneys are the main organ affected, but no serious safety issues have been reported. This indicates that the treatment is generally well-tolerated. As this is the first time \[18F\]RP-115 is being tested in humans, the primary goal is to ensure its safety before conducting further tests. Participants might experience minor side effects, but these are usually manageable and not serious. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about [18F]RP-115 because it offers a new way to study dementia, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). Unlike current treatments that focus on alleviating symptoms, [18F]RP-115 is a PET tracer used to visualize and compare brain activity in patients with these conditions. It specifically targets EAAT2, a protein involved in glutamate regulation, which is crucial for brain function. By providing clearer images of the brain's activity, [18F]RP-115 could help us better understand these diseases and lead to more targeted therapies in the future.

What evidence suggests that this PET agent is effective for diagnosing dementia?

Research has shown that the PET agent [18F]RP-115 might help detect early brain changes in Alzheimer's disease (AD) and frontotemporal dementia (FTD). It uses a special marker to highlight affected brain areas. This trial includes different cohorts: one with AD patients, one with FTD patients, and one with age-matched cognitively normal controls, all receiving [18F]RP-115. Although human studies have provided limited data, similar PET agents have identified brain activity changes that other scans might miss. This suggests that [18F]RP-115 could improve early dementia diagnosis by revealing brain function changes before major symptoms appear. Early studies indicate this method could enhance understanding of these diseases. ^{4 5 6 7 8}

Who Is on the Research Team?

David Wilson, MD, PhD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for adults aged 40-75 with suitable arteries for catheterization, non-smokers, not on CNS drugs for three weeks, and those who can consent or have a guardian to do so. Pregnant or breastfeeding individuals and those with certain medical devices or conditions that could affect the study's outcome are excluded.

Inclusion Criteria

I do not have any visible physical disorders.

Ability to provide written informed consent and willing to comply with protocol requirements, or has a legal authorized representative/guardian who provides surrogate informed consent

My arm's main arteries are suitable for a catheter procedure.

Exclusion Criteria

You cannot have a magnetic resonance imaging (MRI) scan because you have a pacemaker, implantable metallic device, or severe fear of enclosed spaces.

Participants who are breast-feeding

Have a medical condition or other circumstances that in the opinion of the project physicians would significantly decrease chances of obtaining reliable data, achieving the study objective or completing the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dosimetry and Safety Assessment

Whole-body PET/MRI scan conducted immediately after [18F]RP-115 injection to establish safety and dosimetry in healthy volunteers

3.5 hours per session, over a year

Multiple sessions (in-person)

Diagnostic Performance Evaluation

Utilize [18F]RP-115 to assess regional cerebral binding differences in healthy volunteers compared to AD and FTD patients

3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a follow-up 24-48 hours after [18F]RP-115 administration

1-2 days post-administration

What Are the Treatments Tested in This Trial?

Interventions

• [18F]RP-115

Trial Overview [18F]RP-115 PET/MRI or PET/CT along with MRI is being tested to see if it can detect early brain changes in Alzheimer's and frontotemporal dementia patients. This first-in-human study evaluates the safety and diagnostic capabilities of this new imaging agent.

How Is the Trial Designed?

Group I: Cohort 2C - [18F]RP-115 in patients with FTD Experimental Treatment 1 Intervention

Comparison of \[18F\]RP-115 PET binding between AD patients and age-matched cognitively normal controls and between AD and FTD

Group II: Cohort 2B - [18F]RP-115 in patients with AD Experimental Treatment 1 Intervention

Comparison of \[18F\]RP-115 PET binding between AD patients and age-matched cognitively normal controls and between AD and FTD

Group III: Cohort 2A - [18F]RP-115 in age-matched controls Experimental Treatment 1 Intervention

Comparison of \[18F\]RP-115 PET binding between AD patients and age-matched cognitively normal controls and between AD and FTD

Group IV: Cohort 1 - dosimetry of [18F]RP-115 in healthy volunteers Experimental Treatment 1 Intervention

Establish \[18F\]RP-115 safety in the clinic with male and female PET imaging.

Who Is Running the Clinical Trial?

David Wilson

Lead Sponsor

Trials

1

Recruited

100+

Rio pharmaceuticals Inc.

Collaborator

Trials

1

Recruited

100+

Published Research Related to This Trial

The modified synthesis of [18F]AV1451 allows for the production of high-yield doses (202 ± 57 mCi) with excellent radiochemical purity (98 ± 1%), making it suitable for clinical imaging of tau deposits in Alzheimer's disease.

This new method simplifies the production process by using only 0.5 mg of precursor and automating the synthesis, which enhances efficiency and accessibility for clinical tau PET studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An updated radiosynthesis of [18F]AV1451 for tau PET imaging. Mossine, AV., Brooks, AF., Henderson, BD., et al.[2022]

Recent advancements in molecular biology and genetics have led to the development of specific biomarkers and imaging techniques, such as amyloid and tau PET scans, which allow for the early detection and differentiation of Alzheimer's disease and other dementias.

These imaging methods, including FDG PET and dopamine transporter SPECT, provide valuable insights into brain metabolism and function, enhancing diagnostic accuracy and potentially guiding treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What is New in Nuclear Medicine Imaging for Dementia. Topçuoğlu, ES., Akdemir, ÜÖ., Atay, LÖ.[2023]

The production of [18F] AV-45 for PET imaging of Alzheimer's disease is efficient and reliable, with an average synthesis time of 52 minutes and a high radiochemical purity of over 95%.

PET/CT imaging using [18F] AV-45 showed significantly increased uptake in specific brain regions of Alzheimer's patients, particularly in the posterior cingulate gyrus, indicating its potential as a diagnostic tool for evaluating Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simple Synthesis of [18F] AV-45 and its Clinical Application in the Diagnosis of Alzheimer's Disease. Zhang, QZ., Yilihamu, N., Li, YB., et al.[2023]

The study identified that the reversible two tissue compartment model (2T4k_VB) is more effective for measuring tau load in Alzheimer's disease patients, while a simpler model (1T2k_VB) was preferred for most controls, indicating that tau accumulation may require more complex modeling in affected individuals.

The research demonstrated strong correlations between different modeling approaches for measuring tau load, suggesting that standardized uptake value ratios (SUVr) can reliably reflect tau accumulation, which is crucial for understanding Alzheimer's disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantification of Tau Load Using [18F]AV1451 PET. Golla, SSV., Timmers, T., Ossenkoppele, R., et al.[2019]

Positron emission tomography (PET) is a valuable tool for detecting early functional changes in the brain associated with Alzheimer's disease (AD), even before structural changes are visible on traditional imaging like MRI.

The review focuses on various (18)F- and (11)C-labelled PET tracers that can help in diagnosing AD early, understanding its pathophysiology, and monitoring treatment effects, highlighting their potential in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiopharmaceuticals for positron emission tomography investigations of Alzheimer's disease. Någren, K., Halldin, C., Rinne, JO.[2021]

The new fluorine-18 radiotracer [18F]Flotaza shows high binding affinity for amyloid β plaques in Alzheimer's disease, making it effective for imaging these plaques in the brain, with a Ki value of 1.68 nM.

In a study involving post-mortem human brain tissues from Alzheimer's patients, [18F]Flotaza demonstrated a strong correlation with anti-Aβ immunostains and a high ratio of binding in affected gray matter compared to white matter, indicating its potential utility in clinical PET imaging of Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and evaluation of [18F]Flotaza for Aβ plaque imaging in postmortem human Alzheimer's disease brain. Kaur, H., Felix, MR., Liang, C., et al.[2023]

The PET tracer 18F-PI-2620 effectively detects tau pathology in Alzheimer's disease patients, showing significantly higher binding in brain regions associated with tau deposition compared to healthy controls, indicating its potential as a diagnostic tool.

The administration of 18F-PI-2620 was found to be safe and well tolerated, with imaging results demonstrating a strong correlation between tau uptake and cognitive impairment, suggesting its utility in assessing disease severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tau PET imaging with 18F-PI-2620 in Patients with Alzheimer Disease and Healthy Controls: A First-in-Humans Study. Mueller, A., Bullich, S., Barret, O., et al.[2022]

Positron emission tomography (PET) using FDG is crucial for measuring regional cerebral glucose metabolism in Alzheimer's disease, revealing specific areas of reduced metabolism that can help in early diagnosis and understanding of the disease.

PET imaging can also assess neuroinflammation and amyloid deposition using different tracers, making it a versatile tool in dementia research for evaluating brain function and the effectiveness of new treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Positron emission tomography imaging in dementia. Herholz, K., Carter, SF., Jones, M.[2022]

Positron emission tomography (PET) is a valuable tool in diagnosing neurodegenerative disorders like dementia by measuring cerebral glucose metabolism, which aids in early and accurate diagnosis.

PET imaging with various tracers can reveal important biomarkers related to amyloid and tau protein accumulation and neuroinflammation, enhancing understanding of dementia's underlying mechanisms and improving diagnostic accuracy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PET/CT in diagnosis of dementia. Berti, V., Pupi, A., Mosconi, L.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12231855/

18F-FDG PET for the differential diagnosis of Alzheimer's ... This multicenter prospective cohort study aimed to evaluate the value of 18 F-FDG PET for differential diagnosis of Alzheimer's disease (AD) and frontotemporal ...

2. clinicaltrials.ucbraid.org clinicaltrials.ucbraid.org/frontotemporal-dementia

University of California Health Frontotemporal Dementia ... This is a first in human study that will assess the safety and diagnostic performance of [18F]RP-115 (fluorine-18 labeled RP115), a positron ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10852737/

The Added Value of 18-Fluorodeoxyglucose-Positron ... The 18F-FDG-PET is able to identify nearly half of the patients with bvFTD who remain undetected by magnetic resonance imaging.

4. synapse.patsnap.com synapse.patsnap.com/drug/1d0018e19d2e48548624bd3cd501d9a5

RP-115 - Drug Targets, Indications, Patents This more optimal [18F]RP-115 tracer injected activity definition is similar to the amounts used for other established [18F]labeled clinical PET ...

5. researchgate.net researchgate.net/publication/260429995_The_Added_Value_of_18-Fluorodeoxyglucose-Positron_Emission_Tomography_in_the_Diagnosis_of_the_Behavioral_Variant_of_Frontotemporal_Dementia

The Added Value of 18-Fluorodeoxyglucose-Positron ... Methods: The 18F-FDG-PET was performed in 52 patients with suspected bvFTD but lacking characteristic structural neuroimaging results. The ...

6. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT05374278

First-in-Human Evaluation of an Astrocytic Glutamate ... This is a first in human study that will assess the safety and diagnostic performance of [18F]RP-115 (fluorine-18 labeled RP115), a positron emission ...

7. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/369965

First-in-Human Evaluation of an Astrocytic Glutamate ... This is a first in human study that will assess the safety and diagnostic performance of \[18F\]RP-115 (fluorine-18 labeled RP115), a positron ...

8. reporter.nih.gov reporter.nih.gov/project-details/10539917

Project Details - NIH RePORTER In this project we will develop a novel [18F]-labeled PET imaging tracer, RP-115, to evaluate changes in astrocytes in healthy versus cognitively impaired AD ...