Synthesis of an 18F‐labelled high affinity β1‐adrenoceptor PET radioligand based on ICI 89,406

To date, some non‐selective β‐adrenoceptor (β‐AR) positron emission tomography (PET) radioligands are in clinical use, but no PET radioligand for the selective imaging of cardiac β₁‐ARs is clinically available. Therefore, the aim of this study was to develop a potential high‐affinity PET radioligand for the β₁‐subtype of ARs. Here, the synthesis and in vitro evaluation of (S)‐ and (R)‐N‐2‐3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐4‐(2‐fluoro‐ethoxy)‐phenyl]‐urea ( 8a–b ), derivatives of the well‐characterized β₁‐AR selective antagonist, ICI 89,406, are described. The (S)‐isomer 8a shows both higher β₁‐AR selectivity and β₁‐AR affinity than the (R)‐enantiomer 8b (selectivity: 40 800 vs 1580; affinity: K_I1=0.049 nM vs K_I1=0.297 nM). Therefore, the ¹⁸F‐labelled analogue 8e of compound 8a was synthesized. While the direct nucleophilic ¹⁸F‐fluorination of the tosylate precursor 8d produced 8e in low radiochemical yields (?2.9% decay‐corrected) and specific activities (?3.5 GBq/µmol at the end of synthesis (EOS), n=9) the alternative two‐step synthesis of 8e from ethylene glycol di‐p‐tosylate 9 , ¹⁸F]fluoride ion and phenol precursor 8f gave satisfying results (16.4±3.2% radiochemical yield (decay‐corrected), 99.7±0.5% radiochemical purity, 40±8 GBq/µmol specific activity at the EOS within 174±3 min from the end of bombardment (EOB) (n=5)). Copyright © 2006 John Wiley & Sons, Ltd.