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

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 = 36) 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:Twenty-five 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.

- 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.

- Current drug/alcohol abuse or dependence.

- Current use of psychiatric medications.

- NIMH employees and staff

EXCLUSION CRITERIA Phase 2:

- 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.