Alcohol-Supported Cu-Mediated 18F-Fluorination of Iodonium Salts under “Minimalist” Conditions

Abstract

In the era of personalized precision medicine, positron emission tomography (PET) and related hybrid methods like PET/CT and PET/MRI gain recognition as indispensable tools of clinical diagnostics. A broader implementation of these imaging modalities in clinical routine is closely dependent on the increased availability of established and emerging PET-tracers, which in turn could be accessible by the development of simple, reliable, and efficient radiolabeling procedures. A further requirement is a cGMP production of imaging probes in automated synthesis modules. Herein, a novel protocol for the efficient preparation of 18F-labeled aromatics via Cu-mediated radiofluorination of (aryl)(mesityl)iodonium salts without the need of evaporation steps is described. Labeled aromatics were prepared in high radiochemical yields simply by heating of iodonium [18F]fluorides with the Cu-mediator in methanolic DMF. The iodonium [18F]fluorides were prepared by direct elution of 18F− from an anion exchange resin with solutions of the corresponding precursors in MeOH/DMF. The practicality of the novel method was confirmed by the racemization-free production of radiolabeled fluorophenylalanines, including hitherto unknown 3-[18F]FPhe, in 22–69% isolated radiochemical yields as well as its direct implementation into a remote-controlled synthesis unit.

Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer

“…Organic syntheses of both the precursor (MN3PU, 3) and the non-radioactive standard (FMN3PU, 4) were performed as reported elsewhere [ 4 ]. Briefly, the products were formed after the reaction of substituted aniline (1) with isocyanate intermediates ((5), formed in situ by heating the azide (2)) ( Scheme 1 ).…”

“…The key requirements for nucleophilic aromatic substitutions (S N Ar) comprise a suitable leaving group (LG, e.g., NO 2 ), a strong electron-withdrawing group (EWG) and a nucleophile (Nu) with either - ortho (2-position) or - para (4-position) orientation on the aromatic ring. Over the past few years, there has been tremendous development in radiofluorination chemistry involving both activated- and deactivated aryl-rings, including the deoxifluorination of phenols via Ru π-complexes [ 2 ], the substitution of aryl sulfonium salts [ 3 ], as well as iodonium, boronates or stannyl salts mediated by Cu, Ni or Pd catalysts [ 4 ].…”

Application of Hypervalent Iodine Compounds in Advanced Green Technologies (In Press)

“…13) [69]. However, the presence of a copper catalyst, can reverse the regioselectivity of nucleophilic fluorination [70]. The radioligand 39 was obtained by nucleophilic fluorination of iodonium tosylate 38 in good radiochemical yield (Fig.…”

Nucleophilic Synthesis of 6-l-[18F]FDOPA. Is Copper-Mediated Radiofluorination the Answer?

“…In follow-up studies by our group and Neumaier’s group [ 71 ], the minimalist protocol [ 68 ] was used for direct preparation of a series of 2,3- and 4-[ 18 F]labeled phenylalanines in high yields, starting from respective MAI precursors ( Scheme 6 ) without the use of PTC, base or any other additives. The [ 18 F]fluoride retained on the anion-exchange resin was eluted with a solution of the MAI precursor in MeOH/DMF, followed by fluorination reaction in this combination of solvents.…”

“… Preparation of 2, 3 and 4-[ 18 F]labeled phenylalanines via minimalist protocol; radiofluorination: elution of [ 18 F]fluoride from the ion exchange cartridge with a solution of the MAI precursor (21 µmol) in 20% MeOH in DMF (0.6 mL); Cu(MeCN) 4 OTf (21 µmol) in DMF (0.6 mL), 85 °C, 20 min; hydrolysis: 12 M HCl (0.5 mL), 80 °C, 10 min [ 71 ]. …”