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 a 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 AE 5% ([ 18 F]5a) and 47 AE 4% ([ 18 F]5b) (n ¼ 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.