Synthesis of an 18 F‐labelled high affinity β 1 ‐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 β 1 ‐ARs is clinically available. Therefore, the aim of this study was to develop a potential high‐affinity PET radioligand for the β 1 ‐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 β 1 ‐AR selective antagonist, ICI 89,406, are described. The ( S )‐isomer 8a shows both higher β 1 ‐AR selectivity and β 1 ‐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 18 F‐labelled analogue 8e of compound 8a was synthesized. While the direct nucleophilic 18 F‐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 , [ 18 F]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.