Synthesis of (R)- and (S)-[O-methyl-11C]N-[2-[3-(2-cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]-N′-(4-methoxy-phenyl)-urea as candidate high affinity β1-adrenoceptor PET radioligands
✍ Scribed by Stefan Wagner; Marilyn P. Law; Burkhard Riemann; Victor W. Pike; Hans-Jörg Breyholz; Carsten Höltke; Andreas Faust; Otmar Schober; Michael Schäfers; Klaus Kopka
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- French
- Weight
- 148 KB
- Volume
- 48
- Category
- Article
- ISSN
- 0022-2135
- DOI
- 10.1002/jlcr.965
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✦ Synopsis
Molecular imaging and quantification of myocardial b 1 -adrenoceptor (AR) rather than total b-AR density is of great clinical interest since cardiac biopsy studies suggest that myocardial b 1 -AR density is reduced in patients with chronic heart failure whereas cardiac b 2 -AR density may vary. Positron emission tomography (PET), with appropriate radioligands, offers the possibility to assess b-AR density non-invasively in humans. However, no PET radioligand for the selective imaging of cardiac b 1 -ARs is clinically available. Here some derivatives of the well characterized b 1 -AR selective antagonist, ICI 89,406, namely the enantiomers of N-[2-[3-(2-cyano-phenoxy)-2hydroxy-propylamino]-ethyl]-N 0 -(4-hydroxy-phenyl)-urea (5a and 5b) were synthesized and evaluated in vitro. The (R)-isomer 5a was more b 1 -selective but has lower affinity than its (S)-enantiomer 5b (b 1 -AR selectivity: 6100 vs 1240; b 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 AE 5% radiochemical yield (decay-corrected) and 97.4 AE 1.3% radiochemical purity with specific radioactivities of 26.4 AE 9.4 GBq/ mmol within 41.2 AE 3.4 min from the end of bombardment (n=14). 5g and 5h are now