4-[(18)F]Fluorophenylpiperazines by Improved Hartwig-Buchwald N-Arylation of 4-[(18)F]fluoroiodobenzene, Formed via Hypervalent λ(3)-Iodane Precursors: Application to Build-Up of the Dopamine D(4) Ligand [(18)F]FAUC 316

Substituted phenylpiperazines are often neuropharmacologically active compounds and in many cases are essential pharmacophores of neuroligands for different receptors such as D(2)-like dopaminergic, serotoninergic and other receptors. Nucleophilic, no-carrier-added (n.c.a.) (18)F-labelling of these ligands in an aromatic position is desirable for studying receptors with in vivo molecular imaging. 1-(4-[(18)F]Fluorophenyl)piperazine was synthesized in two reaction steps starting by (18)F-labelling of a iodobenzene-iodonium precursor, followed by Pd-catalyzed N-arylation of the intermediate 4-[(18)F]fluoro-iodobenzene. Different palladium catalysts and solvents were tested with particular attention to the polar solvents dimethylformamide (DMF) and dimethylsulfoxide (DMSO). Weak inorganic bases like potassium phosphate or cesium carbonate seem to be essential for the arylation step and lead to conversation rates above 70% in DMF which is comparable to those in typically used toluene. In DMSO even quantitative conversation was observed. Overall radiochemical yields of up to 40% and 60% in DMF and DMSO, respectively, were reached depending on the labelling yield of the first step. The fluorophenylpiperazine obtained was coupled in a third reaction step with 2-formyl-1H-indole-5-carbonitrile to yield the highly selective dopamine D(4) ligand [(18)F]FAUC 316.