Imaging endothelin ET(B) receptors using [18F]-BQ3020: in vitro characterization and positron emission tomography (microPET)

The endothelin (ET) receptor system has been shown to play a role in a number of vascular diseases. We have synthesized 18F-and 11C-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 ET(B) 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 ET(B) receptors we have labeled the selective agonist BQ3020 with 18F. In vitro characterization verified that 18F]-BQ3020 bound with a single subnanomolar affinity (K(D) = 0.34 +/- 0.10 nM, B(max) = 9.23 +/- 3.70 fmol/mg protein) to human left ventricle. Binding of 18F]-BQ3020 to human kidney was inhibited by ET-1 and unlabeled BQ3020 but not by the ET(A) selective antagonist FR139317, confirming that selectivity for the ET(B) receptor was retained. In vitro autoradiography revealed, as expected, high levels of ET(B) receptor densities in lung and kidney medulla, whereas kidney cortex and heart showed lower levels of ET(B) receptor densities. Furthermore, a high level of 18F]-BQ3020 binding was found to colocalize to macrophages in atherosclerotic coronary arteries. MicroPET studies demonstrated high uptake of 18F]-BQ3020 in ET(B) receptor-rich tissue, including lung, liver and kidney. The in vivo biodistribution of 18F]-BQ3020 was comparable to that previously obtained for 18F]-ET-1, supporting our hypothesis that the ET(B) receptor plays a significant role in the uptake of ET-1. In conclusion, 18F]-BQ3020 has retained high affinity and selectivity, allowing imaging of ET(B) receptor distributions in vitro and in vivo in human and animal tissue. Furthermore, in vitro data suggest that 18F]-BQ3020 potentially can be used to image atherosclerotic lesions in vivo using PET.