Neuroinflammation Imaging for Alzheimer's Disease

Overseen By IIya Nasrallah, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Pennsylvania

Disqualifiers: Epilepsy, Head trauma, Nicotine dependence, others

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

Compensation: Varies

Number of Visits: 3

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This research study is being done to learn more about inflammation in the brain using Positron Emission Tomography/Computed Tomography (PET/CT) imaging in people with Alzheimer's Disease/Mild Cognitive Impairment or healthy controls. If the subject agrees to be in this study, she/ he will have a PET/CT scan using the investigational radiotracer \[18F\]NOS. A subject with a specific genetic polymorphism may also agree to be in the sub-study in which she/he will have another PET/CT scan using the investigational tracer \[11C\]PBR28 for comparison with the FNOS \[18F\]NOS scan. For subjects who agree to this sub-study they may undergo the brain PET/CT scan with \[11C\]PBR28 either on the same day as the \[18F\]NOS PET/CT or on another day. The subject may have a screening visit before the PET/CT scan visit if the investigator needs to confirm the subject is able to be in the study. A blood sample will be taken before the scans. Additional blood samples will be taken during the PET scans. Subjects must also agree to have an MRI scan for this research study if she/he has not had a recent scan that the study doctor decides can be used for this study.

Do I need to stop my current medications for this trial?

The trial protocol does not specify whether you need to stop taking your current medications. Please consult with the study team for guidance.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team to understand any specific requirements.

What safety data exists for the neuroinflammation imaging treatment in Alzheimer's Disease?

The safety data for the neuroinflammation imaging treatment, which includes tracers like [11C]PBR28, [18F]NOS, and [18F]6-(2-fluoropropyl)-4-methylpyridin-2-amine, is primarily derived from preclinical studies. [11C]PBR28 has been evaluated in a rat model of herpes encephalitis, showing higher sensitivity in detecting neuroinflammation compared to (R)-(11)C-PK11195. [18F]NOS has been tested in a murine model of lung inflammation and in humans post-heart transplantation, with dosimetry studies indicating its potential for human use. [18F]6-(2-fluoropropyl)-4-methylpyridin-2-amine has been evaluated in a mouse model of iNOS activation, showing favorable properties as a PET tracer. These studies suggest the tracers are promising for imaging neuroinflammation, but comprehensive safety data in humans is limited. ^{1 2 3 4 5}

Is the neuroinflammation imaging treatment safe for humans?

The safety of these imaging agents, such as [11C]PBR28 and [18F]NOS, has been evaluated in animal studies, showing their potential as safe PET tracers for detecting inflammation. However, specific human safety data is limited, and further studies are needed to confirm their safety in humans. ^{1 2 3 4 5}

Is the treatment in the trial 'Neuroinflammation Imaging for Alzheimer's Disease' a promising treatment?

Yes, the treatment is promising because it uses advanced imaging techniques to detect and track neuroinflammation, which is important for understanding and managing Alzheimer's disease. This can help in early diagnosis and monitoring the effectiveness of therapies. ^{1 2 5 6 7}

How does this treatment for Alzheimer's disease differ from other treatments?

This treatment uses a PET imaging tracer to target inducible nitric oxide synthase (iNOS), which is involved in neuroinflammation, making it unique as it focuses on imaging inflammation rather than directly treating symptoms or plaques associated with Alzheimer's disease. ^{1 2 5 6 7}

What data supports the idea that Neuroinflammation Imaging for Alzheimer's Disease is an effective treatment?

The available research does not provide direct evidence that Neuroinflammation Imaging for Alzheimer's Disease is an effective treatment. Instead, the studies focus on using imaging techniques to detect inflammation in the brain, which can help in diagnosing and understanding diseases like Alzheimer's. For example, one study used imaging to measure brain inflammation in Parkinson's disease, showing increased inflammation in patients compared to healthy individuals. However, this does not demonstrate that the imaging itself treats Alzheimer's disease. The research highlights the potential of these imaging methods for diagnosis and monitoring rather than treatment. ^{1 2 5 6 8}

What data supports the effectiveness of the drug used in the Neuroinflammation Imaging for Alzheimer's Disease clinical trial?

Research shows that [18F]NOS PET imaging can effectively measure neuroinflammation in conditions like Parkinson's disease, suggesting it might also be useful for Alzheimer's. Additionally, [18F]PBR-111 has shown potential in imaging neuroinflammation in multiple sclerosis, indicating similar imaging agents could be beneficial for Alzheimer's disease. ^{1 2 5 6 8}

Are You a Good Fit for This Trial?

This trial is for men and women over 55, either healthy or with Alzheimer's/Mild Cognitive Impairment. Healthy participants need a negative amyloid PET scan and an MMSE score of 28+. Those with Alzheimer's should have a positive amyloid PET scan and an MMSE score of 14-27. All must be part of the UPenn ADC cohort, informed about the study's nature, consent in writing, and follow guidelines.

Inclusion Criteria

I am 55 years old or older.

Participants must be informed of the investigational nature of this study and be willing to provide written informed consent and participate in this study in accordance with institutional and federal guidelines prior to study-specific procedures.

A brain amyloid PET scan ≤ 1 year prior to enrollment in this study that is determined to be positive by the study PI.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Imaging and Blood Sampling

Participants undergo PET/CT scans using [18F]NOS and possibly [11C]PBR28, along with blood sampling

1 day

1-2 visits (in-person)

MRI Scan

Participants must have an MRI scan if a recent one is not available

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after imaging procedures

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• [11C]PBR28
• [18F]NOS

Trial Overview The study tests two brain imaging agents ([18F]NOS and [11C]PBR28) using PET/CT scans to understand brain inflammation in Alzheimer’s Disease/Mild Cognitive Impairment versus healthy subjects. Some may also join a sub-study comparing both tracers. Participants will undergo blood tests and possibly an MRI.

How Is the Trial Designed?

Group I: AD/MCI or HC with Genetic Polymorphism Experimental Treatment 1 Intervention

Sub-Study: Subjects have a specific genetic polymorphism andare diagnosed with Alzheimer's Disease (AD)/Mild Cognitive Imparment (MCI) or are healthy volunteers/controls (HC).

Group II: AD/MCI or HC Experimental Treatment 1 Intervention

Main Study: Subjects are diagnosed with Alzheimer's Disease (AD)/Mild Cognitive Imparment (MCI) or are healthy volunteers/controls (HC).

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

The study successfully developed a new PET imaging tracer, [18F]FBAT, which can detect inducible nitric oxide synthase (iNOS) activity in a mouse model of neuroinflammation, indicating its potential as a biomarker for neuroinflammation.

In vivo imaging showed that [18F]FBAT accumulation was significantly higher in LPS-treated mice compared to controls, and this accumulation was reduced by an iNOS inhibitor, confirming the tracer's specificity for iNOS in neuroinflammatory conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Automated Synthesis and Initial Evaluation of (4'-Amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase. Yeh, SH., Huang, WS., Chiu, CH., et al.[2021]

The compound [(18)F]9 was identified as a promising PET tracer for imaging inducible nitric oxide synthase (iNOS), showing higher uptake in the lungs of mice with LPS-induced iNOS activation compared to control mice.

In vivo studies confirmed the specificity of [(18)F]9 for iNOS, as tracer uptake was significantly reduced when a known iNOS inhibitor was used, indicating its potential for accurate imaging of iNOS activation in inflammatory conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and synthesis of 2-amino-4-methylpyridine analogues as inhibitors for inducible nitric oxide synthase and in vivo evaluation of [18F]6-(2-fluoropropyl)-4-methyl-pyridin-2-amine as a potential PET tracer for inducible nitric oxide synthase. Zhou, D., Lee, H., Rothfuss, JM., et al.[2021]

The study demonstrated that 18F-PBR-111 PET imaging can effectively identify neuroinflammation in specific brain regions of cuprizone-treated mice, indicating its potential as a marker for multiple sclerosis (MS) research.

Significant uptake of 18F-PBR-111 was observed in areas associated with neuroinflammation, such as the corpus callosum and striatum, and this uptake correlated with the presence of activated microglia, suggesting its utility for evaluating treatment responses in MS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of 18F-PBR-111 in the Cuprizone Mouse Model of Multiple Sclerosis. Jewells, VL., Yuan, H., Merrill, JR., et al.[2021]

In a pilot study involving 10 adults (6 with Parkinson's disease and 4 healthy controls), researchers found that neuroinflammation, indicated by increased levels of the [18F]NOS radiotracer, was significantly higher in Parkinson's patients compared to healthy individuals.

The study suggests that [18F]NOS PET imaging could be a valuable non-invasive tool for measuring neuroinflammation in early-stage Parkinson's disease, highlighting the role of oxidative stress in the disease's pathology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[18F]NOS PET Brain Imaging Suggests Elevated Neuroinflammation in Idiopathic Parkinson's Disease. Doot, RK., Young, AJ., Nasrallah, IM., et al.[2023]

PET and SPECT imaging techniques are crucial for the early diagnosis and study of Alzheimer's disease (AD) by allowing for the in vivo measurement of key biomarkers associated with the disease.

Several promising radioligands, such as [11C]MP4A and [18F]FDDNP, have shown high selectivity and specificity for binding sites in AD patients, indicating their potential for effective diagnostic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Alzheimer's disease imaging agents for clinical studies. Ryu, EK., Chen, X.[2019]

The study evaluated (11)C-PBR28, a new tracer for imaging neuroinflammation, in a herpes simplex encephalitis model using male Wistar rats, showing it was more sensitive than the commonly used (R)-(11)C-PK11195 in detecting TSPO overexpression in various brain regions.

(11)C-PBR28 was metabolized faster than (R)-(11)C-PK11195, with a half-life of 5 minutes compared to 21 minutes, indicating its potential for quicker imaging results in preclinical research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic Analysis of 11C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-11C-PK11195. Parente, A., Feltes, PK., Vállez García, D., et al.[2017]

The study demonstrated that myocardial (18)F-NOS activity is significantly higher in heart transplant patients experiencing organ rejection, indicating its potential as a marker for assessing iNOS activity related to inflammation.

The (18)F-NOS radiopharmaceutical showed acceptable radiation exposure levels, with the bladder wall being the critical organ, suggesting it could be safely used in humans for monitoring iNOS levels in various diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and dosimetry studies for 18F-NOS as a potential PET radiopharmaceutical for inducible nitric oxide synthase in humans. Herrero, P., Laforest, R., Shoghi, K., et al.[2021]

Neuroinflammation is a key factor in the development of Alzheimer's disease, with increased glial cell activation observed in both animal models and human patients, highlighting its potential role in disease progression.

Current imaging techniques, such as positron emission tomography (PET) and magnetic resonance spectroscopy (MRS), are being explored to non-invasively detect and quantify neuroinflammation, which could improve early diagnosis and therapeutic monitoring in Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo molecular imaging of neuroinflammation in Alzheimer's disease. Chaney, A., Williams, SR., Boutin, H.[2020]

Citations

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

Automated Synthesis and Initial Evaluation of (4'-Amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase. [2021]

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

Design and synthesis of 2-amino-4-methylpyridine analogues as inhibitors for inducible nitric oxide synthase and in vivo evaluation of [18F]6-(2-fluoropropyl)-4-methyl-pyridin-2-amine as a potential PET tracer for inducible nitric oxide synthase. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Assessment of 18F-PBR-111 in the Cuprizone Mouse Model of Multiple Sclerosis. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

[18F]NOS PET Brain Imaging Suggests Elevated Neuroinflammation in Idiopathic Parkinson's Disease. [2023]

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

Development of Alzheimer's disease imaging agents for clinical studies. [2019]

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

Pharmacokinetic Analysis of 11C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-11C-PK11195. [2017]

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

Feasibility and dosimetry studies for 18F-NOS as a potential PET radiopharmaceutical for inducible nitric oxide synthase in humans. [2021]

8. England pubmed.ncbi.nlm.nih.gov

In vivo molecular imaging of neuroinflammation in Alzheimer's disease. [2020]