Opioid Receptor Binding Analysis for Healthy Subjects

Overseen By Erin Schubert

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

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

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This study will enroll up to 60 adults (including 30 females and 30 males) in three cohorts of up to 20 subjects each. In all three groups, \[11C\]carfentanil whole-body PET imaging will be used to examine the central nervous system (CNS) and broader systemic opioid binding in an initial scan session. In the two groups not receiving standard of care medication assisted treatment (MAT) for opioid use disorder (OUD) the effects on \[11C\]carfentanil binding potential of the blockade of opioid binding by the non-selective opioid antagonist naloxone administered parenterally in a second scan session will also be examined. If two scans are completed they can be done on the same day or on different days.

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 carfentanil safe for human use?

Carfentanil is not approved for human use and is extremely potent, being about 10,000 times stronger than morphine. It has been associated with numerous fatalities when used illicitly, and its safety in humans is not established. ^{1 2 3 4 5}

How is the drug Carfentanil unique compared to other treatments?

Carfentanil is unique because it is an extremely potent opioid, about 10,000 times stronger than morphine, and it specifically targets mu opioid receptors in the brain with high affinity. It is primarily used in veterinary medicine to immobilize large animals and is not approved for human use, making it distinct from other opioid treatments. ^{2 3 6 7 8}

Research Team

Jacob Dubroff, MD, PhD

Principal Investigator

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

Eligibility Criteria

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

I am between 18 and 50 years old.

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

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.

Trial Timeline

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

Treatment Details

Interventions

• Carfentanil (Opioid Receptor Agonist)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Findings from Research

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 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]

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]

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]

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]

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]

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]

[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]

References

1. England pubmed.ncbi.nlm.nih.gov

Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Detection of Carfentanil by LC-MS-MS and Reports of Associated Fatalities in the USA. [2017]

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

In vivo evaluation of new carfentanil-based radioligands for the mu opiate receptor. [2022]

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

Synthesis and μ-Opioid Activity of the Primary Metabolites of Carfentanil. [2020]

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

Carfentanil: a narrative review of its pharmacology and public health concerns. [2022]

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

Imaging opiate receptors in the human brain by positron tomography. [2019]

7. Germany 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. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Mu opiate receptors are selectively labelled by [3H]carfentanil in human and rat brain. [2019]