F-18 3F4AP Imaging for Multiple Sclerosis

Overseen By Pedro Brugarolas, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Massachusetts General Hospital

Disqualifiers: Brain disease, MRI/PET contraindications, others

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

Compensation: Varies

Number of Visits: 7

Duration: 5 years

60 Participants Needed

Trial Summary

What is the purpose of this trial?

Our overall objective is to obtain an initial assessment of the potential value of using \[18F\]3F4AP for imaging demyelinating diseases such as multiple sclerosis: * Aim 1) Assess the safety of \[18F\]3F4AP in healthy volunteers and subjects with multiple sclerosis (MS). Hypothesis 1: Administration of \[18F\]3F4AP will result in no changes in vitals or other adverse events. * Aim 2) Assess the pharmacokinetics of a bolus infusion of \[18F\]3F4AP in humans including healthy volunteers and MS patients. Hypothesis 2: the pharmacokinetics of \[18F\]3F4AP at the whole brain level will be similar in controls and MS subjects. The kinetics in demyelinated lesions will be slower than in healthy control areas. * Aim 3) Assess the reproducibility of \[18F\]3F4AP in humans. Hypothesis 3: the test/retest variability of \[18F\]3F4AP within the same subject will be lower than 10%. * Aim 4) Correlate MR brain images with \[18F\]3F4AP PET brain images. Hypothesis 4A: all the lesions seen on the MRI will show increased signal (VT or SUV) on the PET images. Hypothesis 4B: some of the lesions on the MRI will show increased signal (VT or SUV) on the PET but not all. * Aim 5) Correlate \[18F\]3F4AP PET signal with neuropsychological testing in people with MS. Hypothesis 5: increased PET signal (VT or SUV) will correlate with impaired Single Digit Modality Test (SDMT) scores. * Aim 6) Correlate \[18F\]3F4AP PET signal with EDSS score in people with MS. Hypothesis 6: increased PET signal (VT or SUV) will correlate with higher EDSS scores.

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

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment F-18 3F4AP for multiple sclerosis?

The research highlights the importance of advanced imaging techniques, like PET imaging, in monitoring multiple sclerosis, which suggests that F-18 3F4AP, a type of imaging agent, could be useful in assessing disease activity and response to treatment. While the studies do not directly address F-18 3F4AP, they emphasize the potential of imaging in understanding and managing multiple sclerosis. ^{1 2 3 4 5}

How does the drug [18F]3F4AP differ from other treatments for multiple sclerosis?

[18F]3F4AP is unique because it is a PET radiotracer that targets voltage-gated potassium channels, allowing for specific imaging of demyelinated lesions in the brain, which is different from traditional MRI methods that may not provide specific molecular insights into demyelination. ^{4 6 7 8 9}

Eligibility Criteria

This trial is for adults aged 18 to 65 with or without multiple sclerosis (MS) who can consent to the study. It excludes those with brain diseases like tumors or stroke, MRI/PET contraindications such as metal implants, severe claustrophobia, certain chronic diseases, allergy to contrast agents used in imaging, excessive prior radiation exposure, pregnant or lactating women, and any unstable health conditions.

Inclusion Criteria

I understand the study and can give my consent.

Exclusion Criteria

You have had allergic reactions to Dotarem or other gadolinium contrast agents in the past.

Inability to provide written informed consent

I am not pregnant, breastfeeding, and there's no chance I could be pregnant before starting treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Initial assessment including PET and MRI scans to establish baseline measurements

1 week

1 visit (in-person)

Treatment

Administration of [18F]3F4AP and assessment of safety, pharmacokinetics, and imaging correlation

5 years

Multiple visits (in-person) over 5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

1 visit (in-person) for retest

Treatment Details

Interventions

• F-18 3F4AP

Trial Overview [18F]3F4AP is being tested for its ability to image demyelination in MS using PET scans. The study will check if it's safe for humans; compare how it moves through the body of healthy people versus those with MS; ensure consistent results on repeated tests; match PET images with MRI findings and correlate them with neuropsychological test scores and disability levels in MS patients.

Participant Groups

Group I: Multiple sclerosis Experimental Treatment 1 Intervention

F-18 3F4AP PET Scan

Group II: Healthy controls Active Control 1 Intervention

F-18 3F4AP PET Scan

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Findings from Research

Regular monitoring of multiple sclerosis (MS) using contrast-enhanced brain MRI is crucial for assessing the disease's progression and the effectiveness of disease-modifying therapies, with recommendations for scans at 6-month intervals after starting treatment.

The presence of gadolinium-enhancing lesions or new/enlarging T2 lesions on MRI scans can indicate a suboptimal response to therapy, suggesting that a change in treatment may be necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical applications of imaging disease burden in multiple sclerosis: MRI and advanced imaging techniques. Riley, C., Azevedo, C., Bailey, M., et al.[2022]

Monthly T2-weighted and gadolinium-enhanced brain MRI is highly effective for detecting disease activity in relapsing-remitting and secondary progressive multiple sclerosis (MS), making it a valuable primary endpoint in short-term clinical trials.

While MRI can indicate pathological changes, it has limited correlation with disability in established MS, so clinical outcomes should remain the primary focus in definitive trials, with MRI serving as a useful secondary measure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. US National MS Society Task Force. Miller, DH., Albert, PS., Barkhof, F., et al.[2007]

MRI is crucial for diagnosing multiple sclerosis (MS), often confirming the presence and location of lesions suggested by clinical evaluations, and it has largely replaced other diagnostic tests.

Recent advancements in MRI technology may enable quicker imaging and more precise quantification of lesions, which could enhance the evaluation of treatment effectiveness in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple sclerosis: the impact of MR imaging. Wallace, CJ., Seland, TP., Fong, TC.[2015]

Gadolinium-enhanced MRI is crucial for understanding multiple sclerosis (MS) and monitoring disease activity, but its effectiveness can be limited by sensitivity and specificity issues, particularly in detecting low-grade inflammation.

Using a triple dose of gadolinium may improve the detection of MS inflammation, and Gd-enhanced MRI should be part of the initial diagnostic process for patients with early neurological symptoms to predict the progression to clinically definite MS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contrast enhancement and the acute lesion in multiple sclerosis. Rovaris, M., Filippi, M.[2015]

A deep learning model was successfully used to enhance the image quality of accelerated brain MR scans for patients with multiple sclerosis, allowing for faster procedures without significantly compromising the quality of volumetric measurements.

The study found that while there were small differences in volumetric measurements between conventional and deep learning-enhanced fast scans, these differences did not affect the correlation with important patient-reported outcomes related to MS symptoms and disability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Applying Deep Learning to Accelerated Clinical Brain Magnetic Resonance Imaging for Multiple Sclerosis. Mani, A., Santini, T., Puppala, R., et al.[2022]

The novel PET radiotracer [18F]3F4AP showed a favorable biodistribution in healthy human volunteers, with the highest activity in the kidneys, urinary bladder, stomach, liver, spleen, and brain, and it cleared from circulation faster than in previous animal studies.

The average effective dose of [18F]3F4AP was 12.1 μSv/MBq, which is lower than other fluorine-18 radiotracers, indicating a potentially safer profile for human imaging without any reported adverse events during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP. Brugarolas, P., Wilks, MQ., Noel, J., et al.[2023]

The study presents a new method for producing the PET tracer [18F]3F4AP, which is a radiofluorinated version of the drug 4-aminopyridine, aimed at imaging demyelination in multiple sclerosis.

The production process involves an automated synthesizer and a flow hydrogenation reactor, along with standard quality control measures, paving the way for future clinical applications of this tracer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Automated Radiochemical Synthesis of [18F]3F4AP: A Novel PET Tracer for Imaging Demyelinating Diseases. Brugarolas, P., Bhuiyan, M., Kucharski, A., et al.[2019]

The PET tracer [18F]3F4AP shows promising properties for imaging demyelination, including high brain penetration and specificity, making it a potential new tool for assessing myelin repair therapies in neurological diseases.

In primate studies, [18F]3F4AP demonstrated greater sensitivity to focal brain injury compared to traditional imaging methods like [18F]FDG and MRI, indicating its effectiveness in detecting changes associated with demyelination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques. Guehl, NJ., Ramos-Torres, KM., Linnman, C., et al.[2022]

The study used hybrid [18F]florbetapir PET-MR imaging to assess myelin damage in 18 relapsing-remitting MS patients, revealing that demyelination occurs not only in visible lesions but also in normal-appearing white matter.

The imaging technique effectively measured in-vivo myelin damage, showing a significant correlation between myelin integrity and diffusion metrics, suggesting its potential utility in clinical management of MS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[18F]Florbetapir PET/MR imaging to assess demyelination in multiple sclerosis. Carotenuto, A., Giordano, B., Dervenoulas, G., et al.[2021]

References

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

Clinical applications of imaging disease burden in multiple sclerosis: MRI and advanced imaging techniques. [2022]

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

Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. US National MS Society Task Force. [2007]

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

Multiple sclerosis: the impact of MR imaging. [2015]

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

Contrast enhancement and the acute lesion in multiple sclerosis. [2015]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Applying Deep Learning to Accelerated Clinical Brain Magnetic Resonance Imaging for Multiple Sclerosis. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP. [2023]

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

Automated Radiochemical Synthesis of [18F]3F4AP: A Novel PET Tracer for Imaging Demyelinating Diseases. [2019]

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

Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

[18F]Florbetapir PET/MR imaging to assess demyelination in multiple sclerosis. [2021]