PET Imaging for Alcoholism

Overseen By Robert B Innis, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Mental Health (NIMH)

Must not be taking: Antidepressants, Antipsychotics

Disqualifiers: HIV, Pregnancy, Unstable medical condition, others

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

Compensation: Varies

Number of Visits: 2

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine whether individuals with alcohol use disorder (AUD) have low levels of the brain protein PDE4B, which is also low in those experiencing major depressive episodes. Researchers will use PET scans with 18F-PF-06445974, a radiotracer, to observe any changes in PDE4B levels after 3 to 4 weeks of alcohol abstinence. Participants should have AUD and be actively withdrawing from alcohol in a clinical setting. This research could lead to more effective treatments for AUD in the future. As a Phase 1 trial, the study focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new approach.

Will I have to stop taking my current medications?

The trial requires that participants must not have taken antidepressants or antipsychotic medications in the week before or during their hospital stay. For other medications, the protocol does not specify, so it's best to discuss with the trial team.

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

Research shows that the experimental tracer 18F-PF-06445974 targets a specific protein called PDE4B in the brain. Both human and animal studies have used this tracer to enhance understanding of certain brain functions. In these studies, participants have tolerated the tracer well, with no major side effects reported.

This clinical trial is in the early stages, focusing mainly on safety and determining the right dose. While the treatment appears safe so far, testing continues to ensure it is well-tolerated in humans. For those considering joining this trial, this phase is crucial for understanding how the treatment functions in the human body. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about 18F-PF-06445974 because it offers a new way to understand alcoholism through PET imaging. Unlike traditional treatments that focus on managing symptoms or reducing alcohol intake, this investigational approach uses a radioligand to visualize brain activity and receptor interactions in real-time. This could lead to more personalized treatment plans by identifying specific brain changes in individuals with alcoholism, potentially paving the way for targeted therapies in the future.

What evidence suggests that this PET imaging technique is effective for studying alcohol use disorder?

Research has shown that people with alcohol use disorder (AUD) often have low levels of a brain protein called PDE4B. In animal studies, scientists used a special PET scan tracer to observe that PDE4B levels decreased after alcohol exposure but returned to normal after a few days without alcohol. This suggests that PDE4B levels might increase when people stop drinking. Although more research on humans is needed, these findings indicate that PDE4B could enhance understanding and treatment of AUD. In this trial, all participants will undergo the same PET imaging tests to further investigate PDE4B levels in individuals with AUD. ^{1 5 6 7 8}

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?

This trial is for adults aged 18 to 70 with Alcohol Use Disorder (AUD) who are already enrolled in protocol 14-AA-0181. They will undergo alcohol withdrawal in a clinic for about a month and participate in additional procedures to measure PDE4B levels.

Inclusion Criteria

Each participant must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document

Willingness to complete the study including MRI tests

Participants 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

Clinically significant abnormalities on laboratory testing beyond that expected in participants during alcohol withdrawal. This includes CBC and acute care panel (Na, K, Cl, CO2, creatinine, glucose, urea nitrogen)

Have recent exposure to radiation related to research (e.g., PET from other research) that, when combined with this study, would be above the allowable limits

I cannot lie flat or still for two hours due to physical or psychological reasons.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Alcohol Withdrawal and Initial PET Scan

Participants undergo alcohol withdrawal and have an initial PET scan within the first week of admission

1 week

1 visit (in-patient)

Continued Alcohol Withdrawal and Second PET Scan

Participants continue alcohol withdrawal and have a second PET scan after 3-4 weeks

3-4 weeks

1 visit (in-patient)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 18F-PF-06445974

Trial Overview The study tests if the protein PDE4B is at lower levels during AUD withdrawal and if it increases after abstaining from alcohol. Participants will have PET scans using an experimental tracer, 18F-PF-06445974, to visualize PDE4B, possibly along with MRI scans.

How Is the Trial Designed?

Group I: One-arm Experimental Treatment 1 Intervention

All subjects will receive the same tests.

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

Positron emission tomography (PET) is a highly sensitive imaging technology that can measure the concentration and distribution of radiotracers in the brain, allowing researchers to study neurochemical and metabolic processes without disrupting the system being measured.

PET has been effectively used to investigate the effects of alcohol and other drugs on brain function and neurochemistry in both humans and nonhuman primates, with new microPET technology enabling similar studies in rodents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Positron emission tomography as a tool for studying alcohol abuse. Thanos, PK., Wang, GJ., Volkow, ND.[2021]

Positron emission tomography (PET) is a powerful imaging technique that can detect early functional brain changes due to alcohol consumption, even before structural damage occurs.

Research using PET has shown that cognitive functions can gradually recover with continued abstinence from alcohol, and it has also provided insights into the mechanisms of alcohol's effects and the genetic factors related to alcoholism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring the Brain's Response to Alcohol With Positron Emission Tomography. Volkow, N., Wang, GJ., Doria, JJ.[2020]

Molecular imaging techniques like PET and SPECT have revealed that alcohol use disorder (AUD) is associated with significant changes in brain metabolism and neuroinflammation, particularly highlighting the role of GABA A-type receptors and the microglial marker translocator protein (TSPO).

Studies indicate that AUD patients show impaired dopamine synthesis and release, which may contribute to the disorder, while opioid receptor antagonists may help mitigate neuroinflammation, suggesting potential avenues for treatment development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular Imaging Studies of Alcohol Use Disorder. Bach, P., de Timary, P., Gründer, G., et al.[2023]

In a study of 25 patients with alcohol-related cognitive impairment (ARCI) and Wernicke encephalopathy (WE), significant brain hypometabolism was observed, particularly in the prefrontal medial cortex, prefrontal lateral cortex, and anterior cingulate cortex, indicating these areas are most affected by alcohol use disorder.

The study found that 72% of patients exhibited severe hypometabolism in the prefrontal medial cortex, suggesting that this brain region is crucial for understanding cognitive impairments related to alcohol use, and that the patterns of hypometabolism were similar between ARCI and WE patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain 18FDG-PET pattern in patients with alcohol-related cognitive impairment. Clergue-Duval, V., Questel, F., Azuar, J., et al.[2021]

In a study using [18F]-FDG microPET imaging on alcohol-drinking rats, it was found that alcohol significantly reduces overall brain glucose metabolism, particularly in the parietal cortex and cerebellum, indicating a direct impact of alcohol on brain function.

Long-term alcohol consumption leads to tolerance, as evidenced by diminished effects on glucose metabolism in long-term drinkers compared to alcohol-naïve and short-term drinkers, while some brain regions showed increased activity, suggesting complex changes in brain function during addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in cerebral [18F]-FDG uptake induced by acute alcohol administration in a rat model of alcoholism. Gispert, JD., Figueiras, FP., Vengeliene, V., et al.[2018]

Positron emission tomography (PET) studies have revealed that alcohol's rewarding effects are linked to changes in various neurotransmitter systems, including dopamine and GABA, as well as its caloric properties, which contribute to alcohol use disorders (AUD).

Research has shown that chronic alcohol exposure leads to significant alterations in brain metabolism and neurotransmitter function, which are associated with compulsive drinking and withdrawal symptoms, highlighting the potential for PET imaging to inform treatment strategies for AUD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurochemical and metabolic effects of acute and chronic alcohol in the human brain: Studies with positron emission tomography. Volkow, ND., Wiers, CE., Shokri-Kojori, E., et al.[2018]

In a study of 30 non-treatment-seeking alcoholics, aripiprazole (15 mg for 14 days) significantly reduced heavy drinking compared to a placebo, indicating its potential efficacy in promoting abstinence.

Brain imaging results showed that aripiprazole blunted activation in the right ventral striatum in response to alcohol cues, suggesting that it may alter the brain's response to alcohol-related stimuli.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of aripiprazole on cue-induced brain activation and drinking parameters in alcoholics. Myrick, H., Li, X., Randall, PK., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT07027839

NCT07027839 | Acute Effects of Alcohol on PET Imaging ... Using the PET radioligand [18F]PF-06445974 (Hereafter referred to as [18F]PF974) to measure PDE4B binding in the brain, 14-AA-0181 participants will be scanned ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39285225/

PET imaging in rat brain shows opposite effects of acute and ... This study imaged rats with the PDE4B-preferring positron emission tomography (PET) radioligand [ 18 F]PF-06445974 following acute and chronic ethanol ...

3. ctv.veeva.com ctv.veeva.com/study/pet-imaging-of-phosphodiesterase-4b-pde4b-in-alcohol-use-disorder

PET Imaging of Phosphodiesterase-4B (PDE4B) in Alcohol ... Using the PET radioligand [18F]PF974 to measure the density of PDE4B, AUD participants will be scanned twice: 1) within one week of admission, and 2) after 3-4 ...

4. reporter.nih.gov reporter.nih.gov/search/IJhW3D-f7EWn1y0kG3Mbvg/project-details/11194724

RePORT RePORTER - National Institutes of Health (NIH) | In a rat model of alcohol dependence, [18F]PF-06445974 brain uptake was significantly reduced at 5 hours post-exposure and normalized by 3 days. This reduction ...

5. researchgate.net researchgate.net/publication/361703746_First-in-human_evaluation_of_18F-PF-06445974_a_PET_radioligand_that_preferentially_labels_phosphodiesterase-4B

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

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06795581?cond=Alcohol%20Use%20Disorder&viewType=Table&rank=8

PET Imaging of Phosphodiesterase-4B (PDE4B) in Alcohol ... To find out (1) if PDE4B levels are lower in people who are withdrawing from AUD and (2) if their PDE4B levels go up after they abstain from alcohol for 3 to 4 ...

7. jnm.snmjournals.org jnm.snmjournals.org/content/65/supplement_2/241480

Novel PET radioligand [18F]PF-06445974 targets PDE4B, and ... We developed [ 18 F]PF-06445974 (PF974) as a radioligand that preferentially binds to PDE4B to study cAMP signaling in humans and animals and as a potential ...

8. trial.medpath.com trial.medpath.com/clinical-trial/bfd0c8ff29c7e292/nct06795581-pet-imaging-pde4b-alcohol-use-disorder

PET Imaging of Phosphodiesterase-4B (PDE4B) in Alcohol ... Using the PET radioligand \[18F\]PF974 to measure the density of PDE4B, AUD participants will be scanned twice: 1) within one week of admission, and 2) after 3- ...