[125I]‐PD 151242: a selective radioligand for human ETA receptors

Our aim was to synthesize a new endothelin ETA selective radioligand, [125I]‐PD 151242 and characterize the compound in human vascular tissue. Binding of [125I]‐PD151242 to sections of human aorta was time‐dependent and reached equilibrium after 120 min at 23°C with an association rate constant of 1.26 ± 0.17 × 108 M−1 min−1 (n = 3 individuals ± s.e.mean). The binding was reversible at 23°C with an observed dissociation rate constant of 0.0025 ± 0.0006 min−1 (n = 3). Saturation binding assays using [125I]‐PD151242 revealed a single population of high affinity ET receptors (n = 3) in aorta (KD = 0.76 ± 0.17 nM; Bmax = 5.98 ± 1.56 fmol mg−1 protein), pulmonary (KD = 1.75 ± 0.20 nM; Bmax = 12.78 ± 1.39 fmol mg−1 protein) and coronary arteries (KD = 0.51 ± 0.07 nM; Bmax = 44.9 ± 1.67 fmol mg−1 protein). ETA selective ligands competed for [125I]‐PD151242 binding in aorta with nanomolar affinity (BQ123, KD = 0.41 ± 0.26 nM; FR139317, KD = 0.55 ± 0.11 nM) whereas the ETB selective compound, BQ3020, competed with micromolar affinity (KD = 1.36 ± 0.25 μm). In isolated coronary arteries, PD151242 was a functional antagonist and caused a significant, parallel rightward shift of the ET‐1 dose‐response curve with a pA2 value of 5.92 (n = 5) and a slope of unity. The high affinity and selectivity of [125I]‐PD151242 for ETA receptors will facilitate the characterization of this sub‐type in human tissues.