[18F]PF-06445974 PET Imaging for Depression
Recruiting in Palo Alto (17 mi)
Overseen byRobert B Innis, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
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
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.
12345How 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.
678910Eligibility 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
+15 more
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.
+15 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: one armExperimental Treatment3 Interventions
All subjects will receive the same testsGroup D will have a baseline and block with apremilastGroup A \& D will have a lung scan
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Institute of Mental Health (NIMH)Lead Sponsor
References
SPECT and PET imaging in mood disorders. [2016]Single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies are yielding a picture of clinical depression as a disorder associated with dysfunction in specific brain regions. These data support the view of depression as a disease of the brain in general and of the frontal and temporal lobes in particular. Frontal lobe hypometabolism is emerging as a common final pathway for most types of primary and secondary depression, regardless of the original cause. The severity of depression is often related to the degree of frontal hypometabolism, and preliminary studies indicate that the hypometabolism normalizes after treatment in concert with the patient's improved mood. Primary depression also is associated with abnormal activation of key brain areas, including discrete aspects of the frontal and temporal lobes, the amygdala, and the cingulate gyrus. Several areas of research are currently under way using SPECT or PET to explore further the neuroanatomy of depression.
Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. [2022]Neuroimaging investigations reveal changes in glucose metabolism (fluorine-18-fluorodeoxyglucose positron emission tomography [PET]) associated with response to disparate antidepressant treatment modalities, including cognitive behavior therapy (CBT), antidepressant pharmacotherapies, and deep brain stimulation. Using a nonrandomized design, the authors previously compared changes following CBT or paroxetine in depressed patients. In this study, the authors report changes in fluorine-18-fluorodeoxyglucose PET in responders to CBT or venlafaxine during a randomized controlled trial.
Update on PET imaging biomarkers in the diagnosis of neuropsychiatric disorders. [2020]To give an update on recent imaging studies probing positron emission tomography (PET) as a tool for improving biomarker-guided diagnosis of neuropsychiatric disorders.
Positron emission tomography imaging in depression: a neural systems perspective. [2022]PET measures of regional glucose metabolism, although chemically nonspecific, are sensitive indices of brain function in the untreated state and following disparate treatments. The continued development of imaging and multivariate statistical strategies is expected to provide an important perspective toward the full characterization of the depression phenotype at the neural systems level. An additional goal is the development of routine, brain-based clinical algorithms that optimize diagnosis and treatment of individual depressed patients.
Deconstructing depression by machine learning: the POKAL-PSY study. [2023]Unipolar depression is a prevalent and disabling condition, often left untreated. In the outpatient setting, general practitioners fail to recognize depression in about 50% of cases mainly due to somatic comorbidities. Given the significant economic, social, and interpersonal impact of depression and its increasing prevalence, there is a need to improve its diagnosis and treatment in outpatient care. Various efforts have been made to isolate individual biological markers for depression to streamline diagnostic and therapeutic approaches. However, the intricate and dynamic interplay between neuroinflammation, metabolic abnormalities, and relevant neurobiological correlates of depression is not yet fully understood. To address this issue, we propose a naturalistic prospective study involving outpatients with unipolar depression, individuals without depression or comorbidities, and healthy controls. In addition to clinical assessments, cardiovascular parameters, metabolic factors, and inflammatory parameters are collected. For analysis we will use conventional statistics as well as machine learning algorithms. We aim to detect relevant participant subgroups by data-driven cluster algorithms and their impact on the subjects' long-term prognosis. The POKAL-PSY study is a subproject of the research network POKAL (Predictors and Clinical Outcomes in Depressive Disorders; GRK 2621).
A 18F-MPPF PET normative database of 5-HT1A receptor binding in men and women over aging. [2022]Neurotransmission imaging studies require normative data for the statistical assessment of neurophysiologic dysfunctions. 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine (18F-MPPF) is a specific serotonin 5-HT1A antagonist PET tracer recently characterized, modeled, and used for clinical research to explore abnormalities in the serotoninergic system. Our study reports, to our knowledge, the first large normative imaging database of 18F-MPPF binding potential (BP) over aging, for both males and females.
Whole-body biodistribution and dosimetry estimates of a novel radiotracer for imaging of serotonin 4 receptors in brain: [¹⁸F]MNI-698. [2016]A new radiotracer for imaging the serotonin 4 receptors (5-HT4) in brain, [¹⁸F]MNI-698, was recently developed by our group. Evaluation in nonhuman primates indicates the novel radiotracer holds promise as an imaging agent of 5-HT4 in brain. This paper aims to describe the whole-body biodistribution and dosimetry estimates of [¹⁸F]MNI-698.
Development of a 18F-labeled PET radioligand for imaging 5-HT1B receptors: [18F]AZ10419096. [2023]Label="INTRODUCTION">In the last decade PET has been useful in studying and understanding the 5-HT1B receptor. [11C]AZ10419369 and [11C]P943 have been applied as radioligands in these studies. Both use carbon-11 (t1/2 = 20.4 min) as radionuclide, which limits the application to PET centres that have an on-site cyclotron and radiochemistry facilities. In this paper we report the synthesis and initial evaluation of the first fluorine-18 PET radioligand to image 5-HT1B receptors in brain, [18F]AZ10419096.
Synthesis and preclinical evaluation of [18F]FSL25.1188, a reversible PET radioligand for monoamine oxidase-B. [2020]Carbon-11 labeled SL25.1188 is a promising reversible monoamine oxidase-B (MAO-B) radioligand that was recently translated for human positron emission tomography (PET) imaging. Herein, we report the development of a novel fluorinated derivative, namely, [18F](S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxymethyl)oxazolidin-2-one ([18F]FSL25.1188; [18F]6), as a candidate 18F-labeled MAO-B radioligand, and, its subsequent preclinical evaluation in non-human primates (NHP). [18F]6 was produced and isolated (>6 GBq) with high radiochemical purity (>99%), and molar activity (>100 GBq/µmol at time of injection). Autoradiography studies conducted in post-mortem human brain sections revealed [18F]6 binding in MAO-B rich regions. PET imaging study of [18F]6 in NHP showed high brain uptake (SUV > 2.5) as well as a regional brain radioactivity distribution in accordance with MAO-B expression. [18F]6 displayed favorable in vivo kinetics, with an early peak in the time-activity curve followed by progressive wash-out from the NHP brain. Specificity of [18F]6 was investigated in a pre-treatment study with l-deprenyl (1.0 mg/kg) wherein reduced radioligand uptake was observed in all MAO-B rich regions. Results from the current preclinical investigation suggests [18F]6 is a promising MAO-B PET radioligand. Further evaluation of [18F]6 and structurally related 18F-analogs are underway to identify an optimized candidate for clinical research studies.
Development of radioligands for imaging of brain norepinephrine transporters in vivo with positron emission tomography. [2019]In the central nervous system (CNS) and in the periphery, specific proteins (transporters) are responsible for the regulation of the synaptic concentrations of the major monoamine neurotransmitters, noradrenaline (NE), serotonin (5-HT) and dopamine (DA). Several reports have shown that the expression of these transporters within the CNS may be altered in patients with certain neurodegenerative or neuropsychiatric disorders. Therefore, in the CNS the monoamine transporters are major targets for existing and developmental drugs. The best known drugs targeting these transporters are the selective 5-HT reuptake inhibitors (SSRIs) (e.g. citalopram, Celexa) that are most frequently used in the treatment of clinical depression. Selective NE reuptake inhibitors (NRIs) have also found use for the treatment of depression and other conditions such as attention deficit hyperactivity (ADHD) disorder. Given that the NE transporter (NET) is also a binding site for cocaine and drugs of abuse, there is a great need for a probe to assess the densities of NET in vivo by brain imaging with either positron emission tomography (PET) or single photon emission tomography (SPET). PET in particular has the potential to measure NET densities quantitatively and with high resolution in the human brain in vivo. The quality of a PET image depends crucially on the radioligand used in the emission measurement. Commonly used radionuclides in PET radioligands are carbon 11 (t(1/2) = 20.4 min) and fluorine-18 (t(1/2) = 109.8 min). This review specifically summarizes the present status of the development of (11)C- or (18)F-labeled ligands as tools for imaging NET in brain with PET in support of neuropsychiatric clinical research and drug development.