Summary
Background:
PDE-4D is a protein found in the brain. It helps control chemical signals that affect mood, memory, and thinking. Problems with PDE-4D may play a role in depression and Alzheimer disease. Being able to measure PDE-4D levels in the body would help doctors identify and manage these diseases. Researchers want to find out if a new tracer (a radioactive substance injected during imaging scans) can help them see PDE-4D in people more effectively.
Objective:
To test a new tracer (\[11C\]JMJ-129-d2) during imaging scans of the brain and body in healthy people.
Eligibility:
Healthy people aged 18 years and older. They must have been screened under protocols 01M0254 or 17M0181.
Design:
All participants will give samples of blood and urine. They will have a test of their heart function. A plastic tube will be inserted into a vein in their arm; the new tracer will be given through this tube.
Some participants will have 1 positron emission tomography (PET)/computed tomography (CT scan of their whole body. They will lie on a padded bed that slides into a doughnut-shaped machine; the machine uses x-rays to create images of the inside of the body.
Some participants will have 1 or 2 PET/CT scans of their brain only. Their head will be supported to keep it still during the scan. They will also have a magnetic resonance imaging (MRI) scan of the brain. MRI uses magnetic fields to capture images of the inside of the body. The MRI scan may require a second visit.
All participants will receive a follow-up call to check on their well-being 2 or 3 days after their scans.
Detailed Description
Study Description:
This is a Phase 1, first-in-human, single-site, open-label, sequential cohort study designed to evaluate the safety, biodistribution, metabolic stability, and quantitative brain imaging characteristics of the novel positron emission tomography (PET) radioligand \[11C\]JMJ-129-d2 in healthy volunteers. The study will proceed through staged cohorts including whole-body dosimetry, evaluation of brain imaging performance, and test-retest reproducibility. We hypothesize that \[11C\]JMJ-129-d2 will demonstrate acceptable safety, radiation dosimetry typical of 11C-labeled radioligands, and stable quantitative brain PET measures suitable for reproducible in vivo imaging of Phosphodiesterase 4D (PDE4D).
Objectives:
Primary Objective:
To evaluate the safety and quantitative brain imaging properties of \[11C\]JMJ-129-d2 in healthy volunteers.
Secondary Objectives:
* To estimate whole-body biodistribution and radiation dosimetry.
* To evaluate stability and reliability of regional total distribution volume (VT) in brain.
* To evaluate test-retest reproducibility of brain VT.
Endpoints:
Primary Endpoint:
Regional VT derived from kinetic modeling of dynamic brain PET data using a metabolite-corrected arterial input function.
Secondary Endpoints:
* Organ residence times and estimated effective radiation dose (rem).
* Regional VT time-stability metric in brain.
* Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of regional VT in brain.
Eligibility Criteria
Age Range: 18 years to 105 years
* INCLUSION CRITERIA:
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
* Provision of signed and dated informed consent under this protocol.
* Successful completion of screening under protocol 01M0254 or 17M0181 and confirmation of eligibility.
* Age 18 years or older.
* In good general health as determined by medical history, physical examination, vital signs, laboratory testing, and electrocardiogram.
* Willingness and ability to comply with all study procedures.
* Have had 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.
* Agree to adhere to the lifestyle considerations
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
* Clinically significant abnormalities on EKG or laboratory testing. This includes CBC and acute care panel (Na, K, Cl, CO2, creatinine, glucose, urea nitrogen).
* Any current DSM-5-TR persistent psychiatric disorder, including but not limited to: schizophrenia spectrum and other psychotic disorders; bipolar and related disorders; and depressive disorders.
* History of neurologic illness or injury with the potential to affect study data interpretation.
* History of seizures, other than in childhood and related to fever.
* Recent exposure to radiation (i.e., PET from other research) which when combined with this study would be above the allowable limits.
* Inability to lie flat on camera bed for at least two hours, including claustrophobia and weight greater than the maximum for the scanner (500 lbs).
* HIV Infection.
* Pregnancy or breast feeding.
* Participants must not have substance use disorder or alcohol use disorder.
* Unable to travel to the NIH.
* Are unable to have an MRI scan (e.g., because of pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, shrapnel fragments, or metal fragments in the eye.
* Known hypersensitivity to phosphodiesterase-4 (PDE-4) inhibitors (e.g. apremilast, roflumilast, crisaborole).
* Current use of any PDE4 inhibitor (e.g., apremilast, roflumilast, crisaborole), or use within 7 days prior to PET imaging.
* Taking CYP3A4 inhibitors (e.g. grapefruit juice, clarithromycin, erythromycin, ritonavir); CYP3A4 inducers (e.g. phenobarbital St. John's Wort, rifampicin) or oral contraceptives containing gestodene and ethinyl estradiol, which may alter the metabolism and affect the kinetics of the study drug.
EXCLUSION OF CHILDREN
Inclusion of children is not appropriate, because this protocol has more than minimal risk from radiation exposure without the possibility of direct benefit.
EXCLUSION OF PREGNANT OR BREASTFEEDING WOMEN
Pregnant women will be excluded because this protocol involves exposure to ionizing radiation. Lactating women will be excluded because radioisotopes may be excreted in milk. We will perform a urine pregnancy test at screening and prior to all procedures to ensure participants are not pregnant. The test must be negative in order to continue on the study. In addition to completing a negative urine pregnancy test, on the day of PET scanning prior to PET scan procedures, participants of childbearing potential will undergo a clinical pregnancy screening interview with a licensed independent practitioner to confirm lack of pregnancy.
EXCLUSION OF PARTICIPANTS WHO ARE HIV POSITIVE
Persons with HIV infection are excluded because HIV infection itself may change cAMP signaling.