Syntheses and radiofluorination of two derivatives of 5‐cyano‐indole as selective ligands for the dopamine subtype‐4 receptor

Abstract

AbstractTwo fluoroethoxy substituted derivatives, namely 2‐[4‐(2‐(2‐fluoroethoxy)phenyl)‐piperazin‐1‐ylmethyl]indole‐5‐carbonitrile (5a) and 2‐[4‐(4‐(2‐fluoroethoxy)‐phenyl)piperazin‐1‐ylmethyl]indole‐5‐carbonitrile (5b) were synthesized as analogs of the selective D4 receptor ligand 2‐[4‐(4‐fluorophenyl)piperazin‐1‐ylmethyl]indole‐5‐carbonitrile (FAUC 316). In vitro characterization using CHO‐cells expressing different dopamine receptor subtypes gave Ki values of 2.1 (5a) and 9.9 nM (5b) for the dopamine D4 subtype and displayed a 420‐fold D4‐selectivity over D2 receptors for 5b. The para‐fluoroethoxy substituted candidate 5b revealed substantially reduced α1 and serotoninergic binding affinities in comparison to the ortho‐fluoroethoxy substituted compound. In order to provide potential positron emission tomography (PET) imaging probes for the dopamine D4 receptor, 18F‐labelling conditions using [18F]fluoroethyl tosylate were optimized and led to radiochemical yields of 81 ± 5% ([18F]5a) and 47 ± 4% ([18F]5b) (n = 3, decay‐corrected and referred to labelling agent), respectively. Thus, 18F‐fluoroethylation favourably at the para position of the phenylpiperazine moiety of the 5‐cyano‐indole framework proved to be tolerated by D4 receptors and could also be applied to alternative scaffolds in order to develop D4 radioligand candidates for PET with improved D4 receptor affinity and selectivity. Copyright © 2005 John Wiley & Sons, Ltd.