Imaging Endothelin ET B Receptors Using ( 18 F)-BQ3020: In Vitro Characterization and

The endothelin (ET) receptor system has been shown to play a role in a number of vascular diseases. We have synthesized 18 Fand 11 C-labeled radioligands to enable in vivo imaging of the fundamental processes involved in ET receptor pharmacology in normal and diseased tissue using positron emission tomography (PET). One aim is to elucidate the proposed role of the ETB subtype as clearing receptor, removing ET-1 from the circulation, and whether this is an important mechanism to limit the detrimental effects caused by upregulated ET-1 in disease. To image ETB receptors we have labeled the selective agonist BQ3020 with 18 F. In vitro characterization verified that [ 18 F]BQ3020 bound with a single subnanomolar affinity (KD = = 0.34 6 0.10 nM ,B max = = 9.23 6 3.70 fmol/mg protein) to human left ventricle. Binding of [ 18 F]-BQ3020 to human kidney was inhibited by ET-1 and unlabeled BQ3020 but not by the ETA selective antagonist FR139317, confirming that selectivity for the ETB receptor was retained. In vitro autoradiography revealed, as expected, high levels of ETB receptor densities in lung and kidney medulla, whereas kidney cortex and heart showed lower levels of ETB receptor densities. Furthermore, a high level of [ 18 F]-BQ3020 binding was found to colocalize to macrophages in atherosclerotic coronary arteries. MicroPET studies demonstrated high uptake of [ 18 F]-BQ3020 in ETB receptor–rich tissue, including lung, liver and kidney. The in vivo biodistribution of [ 18 F]-BQ3020 was comparable to that previously obtained for [ 18 F]-ET-1, supporting our hypothesis that the ETB receptor plays a significant role in the uptake of ET1. In conclusion, [ 18 F]-BQ3020 has retained high affinity and selectivity, allowing imaging of ETB receptor distributions in vitro and in vivo in human and animal tissue. Furthermore, in vitro data suggest that [ 18 F]-BQ3020 potentially can be used to image atherosclerotic lesions in vivo using PET. Exp Biol Med 231:736–740, 2006