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

Abstract

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. 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. [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% (Po0.05, n ¼ 3) and 55% (Po0.05, n ¼ 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.

Calcitonin Gene-Related Peptide Selectively Relaxes Contractile Responses to Endothelin-1 in Rat Mesenteric Resistance Arteries

“…We confirm the presence of ET A -and ET B -receptors on arterial smooth muscle and sensory-motor nerves and of ET B -receptors on the endothelium (for review, see Davenport, 2002;Masaki, 2004;Johnström et al, 2005;Battistini et al, 2006;Hynynen and Khalil, 2006;Dhaun et al, 2007;Schneider et al, 2007;Kirkby et al, 2008;Opitz et al, 2008;Chichorro et al, 2009). We also document the presence of ET A -receptors on peripheral arterial endothelium.…”

“…These interventions and the ET B -receptor antagonist BQ788 did, however, not modify sensitivity and maximal arterial contractile responses to ET-1. Thus, ET B -mediated scavenging of agonist (Johnström et al, 2005), release of NO and prostaglandins (Tirapelli et al, 2005), and sensorymotor nervous vasodilatation do not contribute to the discrepancy between binding and contractile effects of ET-1. These findings do not exclude that ET-1 can stimulate the endothelium and the sensory-motor nerves.…”

“…This contrasts with the subnanomolar ligand-binding affinities of ET-1 for ET A -and ET B -receptors on cells and cell membranes (Davenport, 2002;Masaki, 2004;Johnström et al, 2005;Battistini et al, 2006;Hynynen and Khalil, 2006;Dhaun et al, 2007;Schneider et al, 2007;Kirkby et al, 2008;Opitz et al, 2008). Opposing Pretreatment with CAPS and the presence of a CGRPreceptor antagonist or of L-NAME plus INDO, increases contractile responses to K ϩ (De Mey et al, 2008;Hilgers and De Mey, 2009).…”

Targeting of Endothelin Receptors in the Healthy and Infarcted Rat Heart Using the PET Tracer18F-FBzBMS

“…ET-A-selective blockade led to a significant reduction of tracer accumulation in the heart but not in the lungs, suggesting that cardiac uptake is predominately mediated by ET-A (27). An 18 F-labeled nonselective tracer for ET-A and ET-B was introduced by Johnström et al (28), and the same group later described a specific tracer for ET-B, 18 F-BQ3020, which showed binding in the lung and kidneys but not in the heart (29). Our agent, 18 F-FBzBMS, has advantages for imaging of the heart in that it combines the longer half-life of 18 F with a selectivity for ET-A as the relevant endothelin receptor in cardiac tissue.…”

Comparison of human ETA and ETB receptor signalling via G-protein and β-arrestin pathways

“…A third antagonist, sitaxentan (Wu et al, 1997), is much more ET A selective than ambrisentan. The optimal receptor selectivity for treatment of PAH remains debatable (Davie et al, 2009) but an ET A selective compound has the advantage of leaving unaffected potentially beneficial vasodilator (Takayanagi et al, 1991) and clearing ET B receptors (Johnström et al, 2005;Kelland et al, 2010) that are present, for example on endothelial cells (Bacon et al, 1996;Gardiner et al, 1994) and expressed at particularly high densities in the lung and kidney (Johnström et al, 2002(Johnström et al, , 2006.…”