Positron emission tomography using 18 F‐labelled endothelin‐1 reveals prevention of binding to cardiac receptors owing to tissue‐specific clearance by ET B receptors in vivo

1 Our aim was to synthesise an 18 F analogue of endothelin‐1 (ET‐1), to dynamically image ET receptors in vivo by positron emission tomography (PET) and to elucidate the function of the ET B subtype as a clearing receptor in organs expressing high densities including kidney and lung. 2 [ 18 F]‐ET‐1 was characterised in vitro and bound with a single subnanomolar affinity ( K D =0.43±0.05 n M , B max =27.8±2.1 fmol mg −1 protein) to human left ventricle ( n =4). 3 The in vivo distribution of [ 18 F]‐ET‐1 in anaesthetised rats was measured using a dedicated small animal PET scanner (microPET) and ex vivo analysis. 4 Dynamic PET data demonstrated that high levels of radioligand accumulated rapidly in the lung, kidney and liver, consistent with receptor binding. The in vivo distribution correlated with the anatomical localisation of receptors detected in vitro using [ 125 I]‐ET‐1. However, the receptor density visualised in the heart was unexpectedly low compared with that predicted from the in vitro measurements. 5 [ 18 F]‐ET‐1 binding in lungs could not be displaced by the ET B selective antagonist BQ788, in agreement with the proposed internalisation of ET‐1 by ET B receptors. In contrast, infusion of BQ788 prior to injecting [ 18 F]‐ET‐1 significantly reduce the amount of radioligand visualised in the ET B rich lung and kidney by 85% ( P <0.05, n =3) and 55% ( P <0.05, n =3), respectively. 6 Under conditions of ET B receptor blockade, the heart could be visualised by microPET imaging. 7 These results suggest that clearance by ET B receptors in the lung and kidney prevents binding of ET‐1 to receptors in the heart.British Journal of Pharmacology (2005) 144 , 115–122. doi: 10.1038/sj.bjp.0706064