[18F]PF-06445974 PET Imaging for Depression

Overseen By Tara N Turon, C.R.N.P.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Mental Health (NIMH)

Must not be taking: Antidepressants, Antipsychotics, Anxiolytics, others

Disqualifiers: Psychotic disorders, Substance use, HIV, others

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

Compensation: Varies

Number of Visits: 6

108 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Major depressive disorder (MDD) is a psychiatric condition. People with MDD have occasional bouts of depressive symptoms; these bouts are called major depressive episodes (MDEs). Researchers want to know if people having MDEs have lower levels of an enzyme called PDE4B in their brains. Primary Objective: To determine whether PDE4B is reduced in the brains of individuals with MDD experiencing a major depressive episode (MDE). Secondary Objectives: To determine the optimal length of scanning and the retest variability and reliability of \[18F\]PF-06445974, and whether PDE4B binding correlates with clinical rating scales. To measure if PDE4B radioligand binding can be blocked by taking apremilast. Eligibility: People aged 18-70 years with MDD. Healthy volunteers are also needed. Design: Participants will have up to 5 clinic visits. Participants will be screened. They will have a physical exam with blood tests. They will have a test of their heart function. Some participants may have a psychiatric assessment; they will answer questions about their state of mind and related topics. Participants will have magnetic resonance imaging (MRI) of the brain. They will lie on a table that slides into a metal cylinder. Participants will have a positron emission tomography (PET) scan. A needle will be used to guide a thin plastic tube (catheter) into a vein in one arm. An experimental substance called a radioactive tracer (\[18F\]PF-06445974) will be injected through the catheter. Participants will lie on a table that slides into a doughnut-shaped machine. The scan will last up to 4 hours with a 15-minute break. Participants blood pressure, heart rate, and breathing will be monitored before, during, and after the PET scan. A second catheter will be inserted in the artery of the wrist so blood can be drawn during the scan. Some participants may return for a second PET scan; have a lung scan or receive apremilast. https://nimhcontent.nimh.nih.gov/start/surveys/?s=KE88DXXPLDFHHTF8

Will I have to stop taking my current medications?

Yes, participants must stop taking certain medications, including antidepressants, antipsychotics, anxiolytics, and sedatives/hypnotics, at least two weeks before the screening visit (five weeks for some specific medications like aripiprazole, brexpiprazole, and fluoxetine).

What data supports the effectiveness of the drug 18F-PF-06445974 for depression?

Research shows that PET imaging, which uses similar compounds, can help identify brain function changes in depression, particularly in areas like the frontal lobe. These changes often normalize with treatment, suggesting that PET imaging can be a useful tool in understanding and potentially guiding treatment for depression. ^{1 2 3 4 5}

How does the drug [18F]PF-06445974 differ from other treatments for depression?

[18F]PF-06445974 is a PET imaging agent used to study depression by targeting specific serotonin receptors in the brain, which is different from traditional depression treatments that typically involve medications like SSRIs (selective serotonin reuptake inhibitors) that alter serotonin levels. This imaging approach helps researchers understand the underlying brain chemistry of depression rather than directly treating symptoms. ^{6 7 8 9 10}

Research Team

Robert B Innis, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Eligibility Criteria

Adults aged 18-70 with Major Depressive Disorder (MDD) and healthy volunteers are eligible for this trial. Participants must be in good health, use contraception if of childbearing potential, have a primary care provider or psychiatrist, and agree to lifestyle considerations. Exclusions include recent suicidal behavior, psychiatric hospitalization within the past year, substance abuse disorders within three months (except caffeine/nicotine), unstable medical conditions, HIV infection, pregnancy, inability to undergo MRI scans or lie still for PET scans.

Inclusion Criteria

My depression score is high enough to qualify.

I am between 18 and 70 years old.

Healthy controls must have their radial artery pulse checked for the presence of adequate ulnar collateral flow and the absence of any metal or foreign objects in both wrists

Exclusion Criteria

Healthy controls with an unstable medical condition that makes participation unsafe

Healthy controls with a history of DSM-5 substance use disorder within the preceding three months

I have been hospitalized for mental health issues within the last year.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Imaging and Testing

Participants undergo MRI and PET scans to measure PDE4B levels, with monitoring of vital signs

1-2 weeks

Up to 5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after imaging and testing

4 weeks

Treatment Details

Interventions

• 18F-PF-06445974

Trial Overview The study is testing an experimental radioactive tracer called [18F]PF-06445974 using PET scans to detect PDE4B enzyme levels in the brain and determine if these levels are lower during major depressive episodes. The process involves up to five clinic visits including screening tests like physical exams and blood tests; MRI scanning; PET scanning with continuous monitoring of vital signs; and possibly a second PET scan.

Participant Groups

Group I: one arm Experimental Treatment 3 Interventions

All subjects will receive the same testsGroup D will have a baseline and block with apremilastGroup A \& D will have a lung scan

Who Is Running the Clinical Trial?

National Institute of Mental Health (NIMH)

Lead Sponsor

Trials

3,007

Recruited

2,852,000+

Findings from Research

SPECT and PET imaging studies indicate that clinical depression is linked to dysfunction in specific brain regions, particularly the frontal and temporal lobes, suggesting that depression is fundamentally a brain disorder.

Frontal lobe hypometabolism is a common feature across various types of depression, with its severity correlating to the severity of depressive symptoms; treatment appears to normalize this hypometabolism alongside mood improvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SPECT and PET imaging in mood disorders. George, MS., Ketter, TA., Post, RM.[2016]

In a study involving 24 patients with major depressive disorder, both cognitive behavior therapy (CBT) and venlafaxine showed comparable response rates, indicating that both treatments can be effective for depression.

Neuroimaging results revealed that responders to either treatment exhibited decreased glucose metabolism in key brain areas, with distinct metabolic changes in the subgenual cingulate cortex and caudate differentiating the effects of CBT and venlafaxine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. Kennedy, SH., Konarski, JZ., Segal, ZV., et al.[2022]

Recent studies highlight the effectiveness of positron emission tomography (PET) imaging in diagnosing neuropsychiatric disorders by assessing regional neuronal activity and neuroreceptor function, particularly in conditions like schizophrenia and depression.

PET imaging also provides valuable insights into neuroinflammatory changes in the brain, which could enhance our understanding of disorders such as schizophrenia and obsessive-compulsive disorder, indicating its potential role in guiding treatment and prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on PET imaging biomarkers in the diagnosis of neuropsychiatric disorders. Hellwig, S., Domschke, K.[2020]

Positron Emission Tomography (PET) scans can effectively measure brain function by assessing regional glucose metabolism, which is crucial for understanding depression both before and after treatment.

The ongoing advancement of imaging techniques and statistical methods aims to create personalized clinical algorithms that enhance the diagnosis and treatment of depression based on individual brain activity patterns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Positron emission tomography imaging in depression: a neural systems perspective. Mayberg, HS.[2022]

A significant challenge in treating unipolar depression is that general practitioners often miss diagnosing it in about 50% of cases, primarily due to overlapping physical health issues.

The proposed POKAL-PSY study aims to improve understanding of depression by analyzing various biological markers and using machine learning to identify subgroups of patients, which could enhance diagnosis and treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deconstructing depression by machine learning: the POKAL-PSY study. Eder, J., Pfeiffer, L., Wichert, SP., et al.[2023]

This study established the first large normative database for the serotonin 5-HT1A antagonist PET tracer 18F-MPPF, involving 53 healthy volunteers aged 20-70, which is crucial for assessing neurophysiological dysfunctions.

The findings revealed that in females, 18F-MPPF binding potential decreases with age (3.6% per decade), while males showed different patterns, indicating the need for sex-specific considerations in neuroimaging studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 18F-MPPF PET normative database of 5-HT1A receptor binding in men and women over aging. Costes, N., Merlet, I., Ostrowsky, K., et al.[2022]

The new radiotracer [¹⁸F]MNI-698 shows promise for imaging serotonin 4 receptors in the brain, with a primary elimination route through urine and the urinary bladder identified as the critical organ for radiation exposure.

Dosimetry estimates indicate that the radiation doses from [¹⁸F]MNI-698 are within safe limits for human clinical trials, but future protocols should consider urinary bladder timing to further reduce absorbed doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole-body biodistribution and dosimetry estimates of a novel radiotracer for imaging of serotonin 4 receptors in brain: [¹⁸F]MNI-698. Tavares, AA., Caillé, F., Barret, O., et al.[2016]

The newly developed fluorine-18 PET radioligand, [18F]AZ10419096, successfully images 5-HT1B receptors in the brain, showing high brain uptake and distribution consistent with receptor densities, making it a promising tool for studying these receptors in vivo.

In tests with nonhuman primates, [18F]AZ10419096 demonstrated high specific binding, as evidenced by an 80% reduction in binding when pretreated with AR-A000002, indicating its potential efficacy for clinical PET studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a 18F-labeled PET radioligand for imaging 5-HT1B receptors: [18F]AZ10419096. Lindberg, A., Nag, S., Schou, M., et al.[2023]

The novel fluorinated derivative [18F]FSL25.1188 shows high radiochemical purity and molar activity, making it a promising candidate for PET imaging of monoamine oxidase-B (MAO-B) in the brain.

Preclinical studies in non-human primates demonstrated that [18F]6 has high brain uptake and specific binding to MAO-B rich regions, indicating its potential efficacy for imaging MAO-B expression in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and preclinical evaluation of [18F]FSL25.1188, a reversible PET radioligand for monoamine oxidase-B. Dahl, K., Bernard-Gauthier, V., Nag, S., et al.[2020]

Monoamine transporters, which regulate neurotransmitter levels in the brain, are crucial targets for drugs treating neurodegenerative and neuropsychiatric disorders, with SSRIs being the most common for depression.

The development of PET imaging using (11)C- or (18)F-labeled ligands can provide high-resolution, quantitative measurements of norepinephrine transporter (NET) densities in the brain, aiding in clinical research and drug development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of radioligands for imaging of brain norepinephrine transporters in vivo with positron emission tomography. Schou, M., Pike, VW., Halldin, C.[2019]

References

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

SPECT and PET imaging in mood disorders. [2016]

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

Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. [2022]

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

Update on PET imaging biomarkers in the diagnosis of neuropsychiatric disorders. [2020]

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

Positron emission tomography imaging in depression: a neural systems perspective. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Deconstructing depression by machine learning: the POKAL-PSY study. [2023]

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

A 18F-MPPF PET normative database of 5-HT1A receptor binding in men and women over aging. [2022]

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

Whole-body biodistribution and dosimetry estimates of a novel radiotracer for imaging of serotonin 4 receptors in brain: [¹⁸F]MNI-698. [2016]

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

Development of a 18F-labeled PET radioligand for imaging 5-HT1B receptors: [18F]AZ10419096. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Synthesis and preclinical evaluation of [18F]FSL25.1188, a reversible PET radioligand for monoamine oxidase-B. [2020]

10. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Development of radioligands for imaging of brain norepinephrine transporters in vivo with positron emission tomography. [2019]