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

Abstract

SummaryTo date, some non-selective b-adrenoceptor (b-AR) positron emission tomography (PET) radioligands are in clinical use, but no PET radioligand for the selective imaging of cardiac b 1 -ARs is clinically available. Therefore, the aim of this study was to develop a potential high-affinity PET radioligand for the b 1 -subtype of ARs. Here, the synthesis and in vitro evaluation of (S)-and, derivatives of the well-characterized b 1 -AR selective antagonist, ICI 89,406, are described. The (S)-isomer 8a shows both higher b 1 -AR selectivity and b 1 -AR affinity than the (R)-enantiomer 8b (selectivity: 40 800 vs 1580; affinity: K I1 ¼ 0:049 nM vs K I1 ¼ 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 (42.9% decay-corrected) and specific activities (43.5 GBq/mmol at the end of synthesis (EOS), n ¼ 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 AE 3.2% radiochemical yield (decay-corrected), 99.7 AE 0.5% radiochemical purity, 40 AE 8 GBq/mmol specific activity at the EOS within 174 AE 3 min from the end of bombardment (EOB) (n ¼ 5)).

Preclinical evaluation of an 18F-labelled β1-adrenoceptor selective radioligand based on ICI 89,406

“…( S )- N -[2-[3-(2-Cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]- N ′-[4-(2-[ 18 F]fluoro-ethoxy)-phenyl]-urea (( S )-[ 18 F]F-ICI) was prepared by a two-step synthesis from ethylene glycol ditosylate, [ 18 F]fluoride ion and the phenol precursor, ( S )- N -[2-[3-(2-cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]- N ′-(4-hydroxy-phenyl)-urea, as described elsewhere [24]. …”

“…Unlabelled ( S )-F-ICI was prepared as described previously [24]. It was dissolved in ethanol/dimethylsulphoxide (DMSO)/water (25/1/50, v/v/v) at 2 µmol·ml −1 for injection into animals.…”

“…We have, therefore, synthesised the fluorinated analogues ( R )- and ( S )- N -[2-[3-(2-cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]- N ′-[4-(2-fluoro-ethoxy)-phenyl]-urea (Fig. 1B) [24]. In vitro studies showed that the ( S )-enantiomer had higher β 1 -AR selectivity and affinity than the ( R )-enantiomer (affinity K i1 =0.049 nM vs K i1 =0.297 nM; selectivity 40,800 vs. 1580) [24].…”

“…1B) [24]. In vitro studies showed that the ( S )-enantiomer had higher β 1 -AR selectivity and affinity than the ( R )-enantiomer (affinity K i1 =0.049 nM vs K i1 =0.297 nM; selectivity 40,800 vs. 1580) [24]. The affinity and selectivity of the ( S )-enantiomer were also higher than those for ( S )-ICI-OMe ( K i1 =0.07, selectivity=1240, respectively) [25].…”

“…The affinity and selectivity of the ( S )-enantiomer were also higher than those for ( S )-ICI-OMe ( K i1 =0.07, selectivity=1240, respectively) [25]. The 18 F-labelled ( S )-analogue [( S )-[ 18 F]F-ICI] was synthesised at a higher specific activity [40 GBq·µmol −1 at end of synthesis (EOS)] [24] than was achieved for ( S )-ICI-OMe (6.5 GBq·µmol −1 at EOS) [25]. …”