Synthesis of an18F-labelled high affinityβ1-adrenoceptor PET radioligand based on ICI 89,406

Abstract

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: KI1=0.049 nM vs KI1=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.