Opioid Receptor Binding Analysis for Healthy Subjects

Overseen By Erin Schubert

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must be taking: Buprenorphine, Methadone

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

Disqualifiers: Pregnancy, Claustrophobia, Epilepsy, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how opioids affect the central nervous system and the body using a special type of scan. Researchers are testing how carfentanil, an opioid, binds to opioid receptors in the brain and body, and how naloxone, a drug that blocks opioid effects, alters that binding. The trial includes three groups: two with individuals who have had opioid use disorder (OUD) and one with healthy individuals. Those who have struggled with opioid use but haven't used opioids in the last 30 days, or healthy individuals who have never had opioid use disorder, might be suitable for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

For Cohort 1, you can continue taking buprenorphine or methadone if you're on a stable dose. For Cohorts 2 and 3, you must not have used certain medications like naltrexone, buprenorphine, or methadone in the past 12 months, and you should avoid medications that interfere with the study. Check with the study team to see if your current medications are allowed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that carfentanil can cause serious side effects such as drowsiness, difficulty breathing, and confusion. Its potency surpasses that of other opioids, posing risks to anyone handling or exposed to it. In this study, researchers use carfentanil in a controlled medical setting, making safety measures crucial. They closely monitor participants to manage any potential side effects. Although carfentanil serves as a radiotracer (a substance that helps track how drugs move in the body), its strength necessitates careful handling. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it could reveal new insights into how opioid receptors function in the brain and body. Unlike current treatment options for opioid use disorder that focus on blocking or reducing opioid effects, this trial uses a radiotracer, [11C]carfentanil, to visualize and analyze opioid receptor binding through PET/CT imaging. This innovative approach may help develop more targeted treatments by showing how different substances interact with these receptors. Additionally, by including the use of naloxone and loperamide in different arms, the trial explores how these substances modify opioid receptor activity, potentially leading to more effective therapeutic strategies.

What evidence suggests that this trial's treatments could be effective?

Studies have shown that [11C]carfentanil effectively images the brain's opioid receptors, helping researchers understand opioid function in the body. In this trial, participants will receive [11C]carfentanil to visualize receptor binding. The imaging technique clearly demonstrates how carfentanil attaches to these receptors, which is crucial for studying opioid effects. In certain trial arms, naloxone, a drug that blocks opioids, will be administered to reverse carfentanil’s effects, ensuring safety during imaging studies. This research aims to enhance understanding of opioid interactions in the body, without focusing on treatment at this stage. ^{6 7 8 9 10}

Who Is on the Research Team?

Jacob Dubroff, MD, PhD

Principal Investigator

University of Pennsylvania, Perelman School of Medicine, Department of Radiology

Are You a Good Fit for This Trial?

This trial is for healthy adults aged 18-50, fluent in English, who can consent to participate. It includes those with opioid use disorder (OUD) on stable medication-assisted treatment (MAT), those with OUD not on MAT, and healthy controls without OUD. Pregnant or breastfeeding women, individuals with certain medical conditions or metal implants incompatible with MRI scans are excluded.

Inclusion Criteria

Cohort 3 (OUD-, Healthy Controls): Fluent in English and able to provide written informed consent in English

Cohort 3 (OUD-, Healthy Controls): Informed of the investigational nature of this study and able to provide written informed consent and participate in this study in accordance with institutional and federal guidelines prior to study-specific procedures

I speak English fluently and can sign consent forms in English.

Exclusion Criteria

I am taking medication for alcohol use disorder or heavy drinking.

Cohort 2 (OUD+/MAT-): Current severe substance use disorder (SUD) other than OUD and /or current treatment for an SUD other than OUD, including nicotine dependence, that would interfere with study procedures and outcome

I have a history of epilepsy, seizures, head injury, or brain tumor.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial PET/CT Imaging

Participants undergo an initial PET/CT scan using [11C]carfentanil to examine opioid receptor binding in the CNS and other organs.

1 day

1 visit (in-person)

Second PET/CT Imaging

For non-MAT groups, a second PET/CT scan is conducted with naloxone pretreatment to assess changes in opioid receptor binding.

1 day

1 visit (in-person)

Optional Third PET/CT Imaging

Healthy Controls may undergo a third PET/CT scan with loperamide pretreatment up to 2 years after initial scans.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after imaging sessions.

1 day to 6 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Carfentanil

Trial Overview The study tests how the body's opioid receptors bind to substances by using PET imaging with [11C]carfentanil. Participants will undergo two scan sessions; one baseline and another after receiving naloxone which blocks opioid binding. The aim is to compare receptor activity between different groups of participants.

How Is the Trial Designed?

Group I: Opioid Use Disorder and Medication Assisted Treatment (OUD+/MAT-) Experimental Treatment 2 Interventions

Study imaging will be performed using a whole-body PET/CT scanner. Each participant will receive ≤ 10 mCi of \[11C\]carfentanil intravenously (approximate range for most studies is anticipated to be 2-10 mCi ). Participants will undergo dynamic PET/CT imaging of the brain and body. The scan will take approximately 90 minutes for each scan session. Study imaging will be performed using a whole-body PET/CT scanner. For the first study scan, participants will receive \[11C\]carfentanil radiotracer alone. For the second study scan approximately 13 mcg/kg of naloxone will be administered by IV prior to the \[11C\]carfentanil injection. If both scans are done the same day, then the naloxone injection will be given before the second scan session and there will be a break between the two scan sessions of approximately 3 hours.

Group II: Opioid Use Disorder Only (OUD+/MAT-) Experimental Treatment 2 Interventions

Study imaging will be performed using a whole-body PET/CT scanner. Each participant will receive ≤ 10 mCi of \[11C\]carfentanil intravenously (approximate range for most studies is anticipated to be 2-10 mCi ). Participants will undergo dynamic PET/CT imaging of the brain and body. The scan will take approximately 90 minutes for each scan session. Study imaging will be performed using a whole-body PET/CT scanner. For the first study scan, participants will receive \[11C\]carfentanil radiotracer alone. For the second study scan approximately 13 mcg/kg of naloxone will be administered by IV prior to the \[11C\]carfentanil injection. If both scans are done the same day, then the naloxone injection will be given before the second scan session and there will be a break between the two scan sessions of approximately 3 hours.

Group III: Healthy Controls (OUD-) Experimental Treatment 3 Interventions

Study imaging will be performed using a whole-body PET/CT scanner. Each participant will receive ≤ 10 mCi of \[11C\]carfentanil intravenously (approximate range for most studies is anticipated to be 2-10 mCi ). Participants will undergo dynamic PET/CT imaging of the brain and body. The scan will take approximately 90 minutes for each scan session. Study imaging will be performed using a whole-body PET/CT scanner. For the 1st study scan, participants will receive \[11C\]carfentanil radiotracer alone. For the 2nd study scan approximately 13 mcg/kg of naloxone will be administered by IV prior to the \[11C\]carfentanil injection. If both scans are done the same day, then the naloxone injection will be given before the 2nd scan and there will be a break between the two scans of approximately 3 hours. For the optional 3rd study scan 4 mg capsule or 30 mL solution standard adult dose of loperamide hydrochloride will be given orally 45-75 minutes prior to the\[11C\]carfentanil injection.

Carfentanil is already approved in United States, European Union for the following indications:

Approved in United States as Carfentanil for:

• Veterinary use for immobilization of certain wild animals

Approved in European Union as Wildnil for:

• Veterinary use for immobilization of certain wild animals

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

Carfentanil is a highly potent synthetic opiate that binds very selectively to mu opiate receptors, making it a powerful tool for studying opiate receptor activity in the brain.

Using Carbon-11-carfentanil and positron emission tomography (PET), researchers found that it specifically binds to areas of the brain known to have high densities of opiate receptors, and this binding can be effectively blocked by naloxone, confirming its specificity and allowing for potential studies of neurological and psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imaging opiate receptors in the human brain by positron tomography. Frost, JJ., Wagner, HN., Dannals, RF., et al.[2019]

Carfentanil, a potent mu opioid receptor agonist used in veterinary medicine, has been found as a contaminant in street heroin, leading to numerous emergency department visits and fatalities in the USA.

From September 2016 to January 2017, carfentanil was detected in 262 postmortem blood samples, with concentrations ranging from 10.2 to 2,000 ng/L, highlighting the need for sensitive detection methods in human specimens to prevent further deaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detection of Carfentanil by LC-MS-MS and Reports of Associated Fatalities in the USA. Shanks, KG., Behonick, GS.[2017]

[3H]Carfentanil binds with high affinity to mu opioid receptors in both human and rat brain tissues, indicating its potential as a reliable radioligand for studying these receptors in PET scans.

The study confirms that [3H]carfentanil primarily interacts with mu opioid receptors, as evidenced by its displacement by known mu agonists like naloxone and morphine, while showing minimal interaction with delta and kappa receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mu opiate receptors are selectively labelled by [3H]carfentanil in human and rat brain. Titeler, M., Lyon, RA., Kuhar, MJ., et al.[2019]

The binding parameter estimates of [(11)C]carfentanil in PET studies show excellent reproducibility, with low variability (less than 6%) and high reliability (intraclass correlation coefficients greater than 0.93) in healthy volunteers.

Both reference tissue and arterial plasma input models yield stable estimates of receptor binding after a scanning duration of 40 minutes, making this a practical timeframe for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Measurement of central mu-opioid receptor binding in vivo with PET and [11C]carfentanil: a test-retest study in healthy subjects. Hirvonen, J., Aalto, S., Hagelberg, N., et al.[2021]

Carfentanil is an extremely potent synthetic opioid, estimated to be 10,000 times stronger than morphine, which raises significant safety concerns for both users and first responders due to its potential for severe toxicity.

Individuals exposed to carfentanil can exhibit opioid toxidrome symptoms and may respond to naloxone, but the exact dosage needed for effective treatment is uncertain, highlighting the need for caution and preparedness among first responders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfentanil: a narrative review of its pharmacology and public health concerns. Leen, JLS., Juurlink, DN.[2022]

Eight new derivatives of [(11)C]carfentanil were tested for their potential as safer mu opioid receptor radioligands, focusing on lower pharmacological activity and improved brain uptake.

While none of the derivatives showed better pharmacokinetics or reduced non-specific binding, some demonstrated acceptable specific binding properties, suggesting they could be safer options for in vivo imaging studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo evaluation of new carfentanil-based radioligands for the mu opiate receptor. Jewett, DM., Kilbourn, MR.[2022]

A new method was developed to accurately measure carfentanil and its metabolite norcarfentanil in small blood samples, showing high sensitivity with detection limits as low as 7.5 pg/mL.

Carfentanil caused significant hypothermia and catalepsy in rats, with effects lasting up to 8 hours, and demonstrated nonlinear accumulation at higher doses, suggesting that impaired clearance in humans could lead to dangerous effects from this highly potent opioid.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats. Bergh, MS., Bogen, IL., Garibay, N., et al.[2021]

Carfentanil, a synthetic opioid much more potent than fentanyl, produces metabolites that retain significant activity at the μ-opioid receptor, which is important for understanding its effects in the body.

The identification and synthesis of these metabolites can enhance the analysis of biological samples from individuals exposed to carfentanil and inform the development of effective treatment protocols for overdose cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and μ-Opioid Activity of the Primary Metabolites of Carfentanil. Hsu, FL., Walz, AJ., Myslinski, JM., et al.[2020]

Citations

1. medrxiv.org medrxiv.org/content/10.1101/2024.12.31.24319819v1.full

[11C]Carfentanil PET Whole-Body Imaging of Mu-Opioid ... [ 11 C]CFN whole- body PET scans are useful for understanding MOR physiology under both baseline and blocking conditions.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0223523425006300

PET imaging of the opioid system using radioligands This review provides a comprehensive overview of the main synthetic approaches utilized for the development of opioid receptor radioligands.

3. fda.gov fda.gov/media/148507/download

Reversal of high potency synthetic opioid overdose Effects of carfentanil, considered to be the most potent synthetic opioid currently known, were reversed with IV bolus naloxone. After carfentanil.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2367693/

Imaging of opioid receptors in the central nervous system - PMC Multicompartmental analysis of [11C]carfentanil binding to opiate receptors in humans measured by positron emission tomography. J Cereb Blood Flow Metab ...

5. jnm.snmjournals.org jnm.snmjournals.org/content/48/2/207

and μ-Opioid Receptors by PET in Lung Carcinoma Patients Results: Increased binding of 11C-MeNTI and 11C-CFN was detected in all tumor types studied. 11C-MeNTI binding in tumor and healthy lung tissue was ...

6. dea.gov dea.gov/stories/2025/2025-05/2025-05-14/carfentanil-synthetic-opioid-unlike-any-other

Carfentanil: A Synthetic Opioid Unlike Any Other Exposure to carfentanil can cause respiratory depression or arrest, drowsiness, disorientation, sedation, pinpoint pupils, and clammy skin. The ...

7. in.gov in.gov/dhs/files/Carfentanil-Fact-Sheet.pdf

Carfentanil Safety for Responders Carfentanil and other fentanyl-related compounds are a serious danger to public safety, first responder, medical, treatment and laboratory personnel. Even a ...

8. dhss.delaware.gov dhss.delaware.gov/dph/php/alerts/dhan377/

Division of Public Health – Delaware Health and Social Services Carfentanil and other fentanyl analogs present a serious risk to public safety, first responders, and medical and laboratory personnel.

9. healthvermont.gov healthvermont.gov/sites/default/files/AAA.Fentanyl-Fact-Sheet_NNEPC_FINAL.pdf

Fentanyl and Carfentanil Exposures in First Responders The evidence to date indicates there is minimal risk to first responders encountering patients who have overdosed on these substances or encountering situations.

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6283219/

Human deaths from drug overdoses with carfentanyl ... Carfentanyl induces similar effects to other opioids, however, due to its potency, it also induces strong side effects such as sedation, respiratory depression, ...