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 or ketoprofen) and/or 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 and/or venous blood samples.

Study Population

Healthy adult volunteers (aged 18 years 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 and/or venous 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, ketoprofen, 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 and/or

venous plasma.