Synthesis of ( R )‐ and ( S )‐[ O‐methyl ‐ 11 C] N ‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐ N ′‐(4‐methoxy‐phenyl)‐urea as candidate high affinity β 1 ‐adrenoceptor PET radioligands

Molecular imaging and quantification of myocardial β 1 ‐adrenoceptor (AR) rather than total β ‐AR density is of great clinical interest since cardiac biopsy studies suggest that myocardial β 1 ‐AR density is reduced in patients with chronic heart failure whereas cardiac β 2 ‐AR density may vary. Positron emission tomography (PET), with appropriate radioligands, offers the possibility to assess β ‐AR density non‐invasively in humans. However, no PET radioligand for the selective imaging of cardiac β 1 ‐ARs is clinically available. Here some derivatives of the well characterized β 1 ‐AR selective antagonist, ICI 89,406, namely the enantiomers of N ‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐ N ′‐(4‐hydroxy‐phenyl)‐urea ( 5a and 5b ) were synthesized and evaluated in vitro . The ( R )‐isomer 5a was more β 1 ‐selective but has lower affinity than its ( S )‐enantiomer 5b ( β 1 ‐AR selectivity: 6100 vs 1240; β 1 ‐affinity: K 1 = 0.288 nM vs K 1 = 0.067 nM). Etherification of the analogous desmethyl precursors, 5e and 5f , respectively, with [ 11 C]iodomethane gave 11 C‐labelled versions of 5a and 5b , namely 5g and 5h , in 44 ± 5% radiochemical yield (decay‐corrected) and 97.4 ± 1.3% radiochemical purity with specific radioactivities of 26.4 ± 9.4 GBq/µmol within 41.2 ± 3.4 min from the end of bombardment ( n = 14). 5g and 5h are now being evaluated as candidate radioligands for myocardial β 1 ‐ARs. Copyright © 2005 John Wiley & Sons, Ltd.