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

Two 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 D 4 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 K i values of 2.1 ( 5a ) and 9.9 nM ( 5b ) for the dopamine D 4 subtype and displayed a 420‐fold D 4 ‐selectivity over D 2 receptors for 5b . The para‐fluoroethoxy substituted candidate 5b revealed substantially reduced α 1 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 D 4 receptor, 18 F‐labelling conditions using [ 18 F]fluoroethyl tosylate were optimized and led to radiochemical yields of 81 ± 5% ( [ 18 F]5a ) and 47 ± 4% ( [ 18 F]5b ) ( n = 3, decay‐corrected and referred to labelling agent), respectively. Thus, 18 F‐fluoroethylation favourably at the para position of the phenylpiperazine moiety of the 5‐cyano‐indole framework proved to be tolerated by D 4 receptors and could also be applied to alternative scaffolds in order to develop D 4 radioligand candidates for PET with improved D 4 receptor affinity and selectivity. Copyright © 2005 John Wiley & Sons, Ltd.