4-[18F]Fluorophenylpiperazines by Improved Hartwig-Buchwald N-Arylation of 4-[18F]fluoroiodobenzene, Formed via Hypervalent λ3-Iodane Precursors: Application to Build-Up of the Dopamine D4 Ligand [18F]FAUC 316

Abstract

Substituted phenylpiperazines are often neuropharmacologically active compounds and in many cases are essential pharmacophores of neuroligands for different receptors such as D2-like dopaminergic, serotoninergic and other receptors. Nucleophilic, no-carrier-added (n.c.a.) 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 D4 ligand [

Hypervalent aryliodine compounds as precursors for radiofluorination

“…[ 18 F]4‐Fluoroiodobenzene has been obtained from the radiofluorination of an ylide prepared from Meldrum's acid, namely, (2,2‐dimethyl‐5,7‐dioxo‐1,3‐dioxocan‐6‐yl)(4‐iodophenyl)iodonium, in dimethyl sulfoxide (DMSO) at 110°C in the presence of t ‐butylammonium bicarbonate in 70% yield (entry 2). This yield is quite similar to that obtained from a symmetrical diaryliodonium salt (60%) (Table , entry 9) and is appreciably higher than that from an unsymmetrical diaryliodonium salt (40%) (Table , entry 8) . [ 18 F]4‐Fluoroiodobenzene prepared from the ylide precursor has been used in a multistep radiosynthesis of a candidate D 4 receptor radiotracer, known as [ 18 F]FAUC 316 (Figure ) .…”

“…[ 18 F]Fluorohalobenzenes have been accessed rapidly in moderate to good yields (Table , entries 1‐10) . Notably, among these labeling synthons, [ 18 F]4‐fluoroiodobenzene (entries 6‐10) can be prepared efficiently and has been applied to the radiosynthesis of several candidate radiotracers through efficient transition metal–mediated coupling reactions.…”

“…Notably, among these labeling synthons, [ 18 F]4‐fluoroiodobenzene (entries 6‐10) can be prepared efficiently and has been applied to the radiosynthesis of several candidate radiotracers through efficient transition metal–mediated coupling reactions. These radiotracers include 18 F‐labeled nucleosides, a D 4 receptor ligand, and a cyclooxygenase 2 inhibitor (Figure ).…”

“…This yield is quite similar to that obtained from a symmetrical diaryliodonium salt (60%) (Table 1, entry 9) 99 and is appreciably higher than that from an unsymmetrical diaryliodonium salt (40%) ( Table 1, entry 8). 101 [ 18 F]4-Fluoroiodobenzene prepared from the ylide precursor has been used in a multistep radiosynthesis of a candidate D 4 receptor radiotracer, known as [ 18 F]FAUC 316 ( Figure 18). 101 This radiotracer was obtained for clinical use in 10% yield after 80 minutes of preparation time.…”

Chemistry for Positron Emission Tomography: Recent Advances in 11C‐, 18F‐, 13N‐, and 15O‐Labeling Reactions

“…[81,132,133,[135][136][137][138][139][140][141][142][143] It is noteworthy that [ 18 F]FPEB synthesized by the SCIDYm ethod was fully automated, thereby resulting in asubstantial improvement (3-10 fold) in the RCY and molar activity compared with the traditional S N Ar method. [81,132,133,[135][136][137][138][139][140][141][142][143] It is noteworthy that [ 18 F]FPEB synthesized by the SCIDYm ethod was fully automated, thereby resulting in asubstantial improvement (3-10 fold) in the RCY and molar activity compared with the traditional S N Ar method.…”