Novel radioligands for PET imaging of the endothelin-A receptor

558 Objectives: Endothelin receptors have been implicated in various diseases such as heart failure, hypertension, atherosclerosis, restenosis, chronic renal failure, as well as some types of cancer. Two analogs of the endothelin-A (ETA) selective antagonist BMS207940 were synthesized in order to investigate their potential as PET radioligands. Methods: [11C]BMS5p was synthesized by reacting a desmethyl indole precursor with [11C]methyl iodide. [18F]FBzBMS was synthesized by nucleophilic displacement on a nitro precursor. For biodistribution studies in mice, [11C]BMS5p or [18F]FBzBMS was injected IV with sacrifice at 5, 15, 30, 60, and 90 min. Organs of interest were harvested and the radioactivity of the organs was counted. A baboon was then imaged in 2 two-part PET studies using either [11C]BMS5p or [18F]FBzBMS. Results: The time for radiosynthesis, HPLC purification, and formulation was 36 min for [11C]BMS5p and 130 min for [18F]FBzBMS. The non-decay corrected radiochemical yield was 1.5% for [11C]BMS5p and 0.5% for [18F]FBzBMS. The average specific activity at EOS was 28,400 mCi/µmol (n=5) for [11C]BMS5p and 349 mCi/µmol (n=7) for [18F]FBzBMS. In mice, both tracers showed highest uptake in the liver with significant radioactivity in the lungs, heart, and kidneys. PET studies in a baboon showed baseline accumulation of both radioligands in the myocardium and lungs. Pretreatment with 1 mg/kg of BMS207940 significantly inhibited the uptake of both radioligands in the myocardium. For both radioligands, the specific binding in baboon myocardium was determined to be 85% at 85 min. Conclusions: Both [11C]BMS5p and [18F]FBzBMS bind selectively to the ETA receptor in vivo. Further development of these radioligands for imaging ETA in humans is warranted. Research Support: NIH CA115532, DK50183, CA092871, CA103175