Evaluation of a Novel PET Radioligand to Image Cyclooxygenase-1 (COX-1)

  • STATUS
    Recruiting
  • End date
    Aug 1, 2023
  • participants needed
    61
  • sponsor
    National Institute of Mental Health (NIMH)
Updated on 18 October 2021
Accepts healthy volunteers

Summary

Background

A radioligand is a radioactive substance that is used to diagnose diseases. A new ligand is called [11C]PS13. This has a small amount of radioactivity that can be detected by a positron emission tomography (PET) scan. If this ligand works well in this study, researchers may be able to use it to better understand and diagnose brain disorders.

Objectives

To evaluate if [11C]PS13 can measure its receptor, which is involved in inflammation. To see if researchers get the same results when scanning a person twice.

Eligibility

Healthy people ages 18 and older who are in Protocol 01-M-0254.

Design

This study requires three visits of 2-5 hours each.

Participants will have 2 PET scans with [11C]PS13.

A needle will guide a small plastic tube (catheter) into an arm vein. The needle will be removed, leaving only the catheter in the vein. The ligand will be injected through the catheter.

The PET scanner is shaped like a doughnut. Participants will lie on a bed that slides in and out of the scanner.

Participants will wear a molded a plastic mask that fits the head.

Another catheter will be put into an artery at the wrist or elbow area.

Vital signs will be monitored during the PET scan. Participants will have a test during the PET scan to monitor heart function.

Participants will have blood and urine tests.

Participants will have 1 magnetic resonance imaging (MRI) scan. The MRI scanner is a metal cylinder surrounded by a strong magnetic field. Participants will lie on a table that slides in and out of the cylinder.

Description

Objective

The cyclooxygenase (COX) system is implicated in the pathophysiology of brain diseases, including Alzheimer s disease and depression, and is a potential biomarker for neuroinflammation. COX is the rate-limiting enzyme in the synthesis of prostaglandins from arachidonic acid and exists as two primary isoforms COX-1 and COX-2. Our laboratory recently developed [(11)C]PS13, a novel PET ligand to selectively image COX-1, and initial PET scans in monkey demonstrated that [11C]PS13 is a promising ligand.

This study has two primary objectives. First, we will determine whether the uptake of [(11)C]PS13 in brain and periphery reflects the distribution of COX-1, as demonstrated by blocking with a COX-1 preferential drug (aspirin) and no effect with a COX-2 selective drug (celecoxib). Second, we will measure the test/retest reproducibility of brain uptake quantified by compartmental modeling and using arterial blood samples.

Study Population

Healthy adult female and male volunteers (age 18 or older) will have either whole body imaging (n = 41) or brain imaging (n = 20).

Design

Phase 1: We will begin with whole body scanning in a single human subject using up to 10 mCi. The aim of this first scan will be to detect a tracer that disproportionately accumulates in a single radiosensitive organ, such as the gonads. If we confirm that radioactivity is fairly widely distributed in the body, higher activities may be injected.

Phase 2:Thirty healthy subjects will have three whole body imaging PET scans using 20 mCi of [11C]PS13. Scan 1 will serve as the baseline scan for comparison to enzyme occupancy studies and will provide dosimetry information. Scan 2 will be an enzyme occupancy study using the COX-2 selective antagonist celecoxib. Scan 3 will be an enzyme occupancy study using the COX-1 preferential antagonist aspirin. Ten healthy subjects will have two whole body imaging PET scans using 20 mCi of [11C]PS13. Scan

1 will serve as the baseline scan, and scan 2 will be an enzyme occupancy study using another potent COX-1 antagonist ketoprofen.

Phase 3: We will perform 15 test retest kinetic brain imaging PET studies with arterial blood sampling and 5 test retest brain PET studies with both arterial and venous blood sampling, using a 20 mCi dose of [(11)C]PS13.

Outcome Measures

For whole body imaging, organ uptake will be quantified as a Standardized Uptake Value (SUV), which normalizes for injected activity and body weight. Blockade by aspirin and celecoxib will be expressed as a percentage of the baseline scan in each subject and plotted relative to the plasma concentration of the drug at time of the PET scan. For dedicated brain imaging, uptake will be quantified as distribution volume (VT) calculated with compartmental modeling and serial concentrations of parent radioligand in arterial plasma.

Details
Condition Adult, Normal Physiology
Clinical Study IdentifierNCT03324646
SponsorNational Institute of Mental Health (NIMH)
Last Modified on18 October 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Age greater than or equal to 18
Able to give written informed consent
Medically and psychiatrically healthy
Enrolled in 01-M-0254 The Evaluation of Participants with Mood and Anxiety Disorders and Healthy Volunteers (PI: Dr. Carlos Zarate)
EXCLUSION CRITERIA All phases
Because non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-1 and/or COX-2, subjects should not have taken NSAIDs for two weeks prior to the PET scan. In addition, aspirin must not have been taken in the prior month, as aspirin irreversibly inhibits COX
Clinically significant laboratory abnormalities based on tests performed under screening protocol 01-M-0254
Any current Axis I diagnosis, based on interview and self-reporting performed under screening protocol 01-M-0254
Positive HIV test
History of medical or neurologic illness or injury with the potential to affect study data interpretation
Recent exposure to radiation related to research (i.e. PET from other research) that, when combined with this study, would be above the allowable limits
Inability to lie flat on camera bed for at least two hours
Pregnancy or breastfeeding
Participants must not have substance use disorder or alcohol use disorder. However, alcohol or cannabis use by themselves are not
exclusion criteria, unless that use impairs function
Current use of psychiatric medications
NIMH employees and staff

Exclusion Criteria

Because aspirin and celecoxib require an acidic environment to be absorbed in the stomach, we will exclude those who have taken proton pump inhibitor (PPI) drugs, H-2 receptor antagonist drugs, and antacid drugs in the last two weeks
additional contraindications to taking COX-1 or COX-2 inhibitors include
history of hypersensitivity reaction to COX inhibitors history of aspirin- or NSAID-induced asthma
history of upper or lower gastrointestinal bleeding, gastritis, peptic ulcer disease, or gastroesophageal reflux disease (GERD)
coagulation disorder
thrombocytopenia
G6PD deficiency
history of gout
history of hepatic or renal impairment
history of cardiovascular disease or presence of cardiovascular risk factors such as hypertension
EXCLUSION CRITERIA Phase 3
Artery check for art line
Unable to have an MRI scan
NIH employees are eligible to participate. NIMH employee participation is
guided by intramural institute policy
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