[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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if people with major depressive disorder (MDD) experience changes in the brain enzyme PDE4B during depressive episodes. Researchers will use a special brain scan with a tracer, [18F]PF-06445974, to compare enzyme levels in those with MDD to healthy volunteers. Participants will help assess if this enzyme could be a target for future treatments. Those who have experienced a major depressive episode for at least four weeks might be suitable candidates. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking insights.

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 prior data suggests that this PET imaging technique is safe for humans?

Research has shown that the radioactive tracer [18F]PF-06445974, used in PET scans to view the enzyme PDE4B, has been tested in both animals and humans. These studies demonstrated its effectiveness in imaging PDE4B in the brain. In early human tests, the tracer was used safely, with generally manageable side effects. However, as this study is in its early stages, understanding that the treatment is still under investigation for its complete safety profile is important. Researchers continue to collect data to fully assess its safety in humans, and the results so far are encouraging. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about [18F]PF-06445974 PET imaging for depression because it offers a unique way to study the brain activity linked to this condition. Unlike current treatments for depression, which often involve medications like SSRIs or SNRIs that target neurotransmitter levels, [18F]PF-06445974 is a radiotracer used in PET scans to visualize specific brain receptors, offering insights into how depression affects brain function. This could lead to a better understanding of the condition and potentially pave the way for new treatment approaches.

What evidence suggests that this PET imaging method is effective for studying depression?

Research shows that the radioligand [18F]PF-06445974, administered to all participants in this trial, can effectively measure the enzyme PDE4B in the brain using PET scans. Studies in humans, rodents, and monkeys have demonstrated that this method accurately measures PDE4B levels. Researchers believe PDE4B plays a role in depression, and measuring it may enhance understanding of major depressive disorder (MDD). Early findings suggest that changes in PDE4B might relate to depression symptoms. This radioligand could serve as a valuable tool for understanding and diagnosing MDD. ^{1 2 3 5 6}

Who Is on the Research Team?

Robert B Innis, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Are You a Good Fit for This Trial?

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.

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

Healthy controls must be able to provide informed consent

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9730922/

First-in-Human Evaluation of 18F-PF-06445974, a PET ... This study sought to determine whether 18F-PF-06445974 could accurately quantify PDE4B in living human brain. Toward this end, PET imaging was performed in ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35772961/

First-in-Human Evaluation of 18F-PF-06445974, a ... - PubMed This study evaluated the properties of the newly developed PDE4B-selective radioligand 18 F-PF-06445974 in the brains of rodents, monkeys, and humans.

3. withpower.com withpower.com/trial/phase-1-depression-1-2023-687ed

[18F]PF-06445974 PET Imaging for Depression In a study involving 24 patients with major depressive disorder, both cognitive behavior therapy (CBT) and venlafaxine showed comparable response rates, ...

4. trialx.com trialx.com/clinical-trials/listings/221285/18fpf-06445974-to-image-pde4b-in-major-depressive-disorder-using-pet/

[18F]PF-06445974 to Image PDE4B in Major Depressive ... Clinical trial for Depression , [18F]PF-06445974 to Image PDE4B in Major Depressive Disorder Using PET.

5. jnm.snmjournals.org jnm.snmjournals.org/content/63/supplement_2/2482

First-in-human evaluation of 18F-PF-06445974, a PET ... PDE4B and PDE4D have the highest expression in brain and may have roles in the pathophysiology and treatment of depression and dementia. This ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03030391

Novel Positron Emission Tomography (PET) Radiotracer to ... Pfizer has developed a new PET ligand, 18F-PF-06445974, to selectively image PDE4B; the ligand has shown promising results in non-human primates. This protocol ...