A Practical One‐Pot Synthesis of Positron Emission Tomography (PET) Tracers via Nickel‐Mediated Radiofluorination

Abstract

Recently a novel method for the preparation of 18F-labeled arenes via oxidative [18F]fluorination of easily accessible and sufficiently stable nickel complexes with [18F]fluoride under exceptionally mild reaction conditions was published. The suitability of this procedure for the routine preparation of clinically relevant positron emission tomography (PET) tracers, 6-[18F]fluorodopamine (6-[18F]FDA), 6-[18F]fluoro-l-DOPA (6-[18F]FDOPA) and 6-[18F]fluoro-m-tyrosine (6-[18F]FMT), was evaluated. The originally published base-free method was inoperative. However, a “low base” protocol afforded protected radiolabeled intermediates in radiochemical conversions (RCCs) of 5–18 %. The subsequent deprotection step proceeded almost quantitatively (>95 %). The simple one-pot two-step procedure allowed the preparation of clinical doses of 6-[18F]FDA and 6-[18F]FDOPA within 50 min (12 and 7 % radiochemical yield, respectively). In an unilateral rat model of Parkinsons disease, 6-[18F]FDOPA with high specific activity (175 GBq μmol−1) prepared using the described nickel-mediated radiofluorination was compared to 6-[18F]FDOPA with low specific activity (30 MBq μmol−1) produced via conventional electrophilic radiofluorination. Unexpectedly both tracer variants displayed very similar in vivo properties with respect to signal-to-noise ratio and brain distribution, and consequently, the quality of the obtained PET images was almost identical.

Improved, one‐pot synthesis of 6‐[18F]fluorodopamine and quality control testing for use in patients with neuroblastoma

“…While isolated yields of [ 18 F]F‐DA were sufficient (29%), deprotection reaction conditions were harsh (hydroiodic acid and temperatures >150°C), and analyses of the final product for the residual copper catalyst or Kryptofix 222 were not included. Zlatopolskiy and coworkers described radiofluorination of an aryl nickel(II) complex by [ 18 F]fluoride in the presence of a hypervalent iodine oxidant. A radiochemically pure product was achieved with a radiochemical yield of 12% (6.3% activity yield).…”

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

“…Transition-Metal-Mediated Aromatic 18 F-Fluorination Significant advances have been achieved in aromatic radiofluorination using transition metals with enhanced reactivity,s electivity,a nd tolerance towards functional groups.T his approach may,t hus,p rovide an alternative route to access [ 18 F]fluoroarenes.In2011, Ritter,Hooker, and co-workers developed an ovel aromatic 18 F-fluorination method based on aP d IV complex (Scheme 25 A). [147][148][149] Copper catalysts are widely used in aromatic fluorination reactions with aryl boronates and arylstannanes.I n2 014, This method was applied in the synthesis of [ 18 F]fluoroestrone, [ 18 F]paroxetine,a nd a 18 F-labeled 5-HT 2C agonist (> 1% RCY).…”

Radiosynthesis of the norepinephrine transporter tracer [18F]NS12137 via copper‐mediated 18F‐labelling

“…Several methods have recently been introduced to improve nucleophilic 18 F‐labelling reactions; for example, the use of iodonium or sulfonium salts enables 18 F‐labelling of nonactivated aromatic compounds. Recently, a new pathway, termed transition metal–mediated 18 F‐fluorination, was introduced to produce 18 F‐labelled arenes with high A m s . This transition metal–mediated synthesis pathway is based on the use of cyclotron‐produced [ 18 F]F − .…”

“…In 2011, Lee et al reported the use of palladium complexes in 18 F‐labelling reactions, but due to the moisture‐sensitive nature of these complexes, a more convenient labelling method was still needed . Nickel‐mediated radiosynthesis followed the next year, but this still required the preparation and proper handling of highly complex precursor molecules, which was found to be cumbersome when designing clinical tracers that had to be synthetized according to good manufacturing practices (GMPs) . In 2013, Ye and Sanford reported the mild copper‐mediated fluorination of aryl stannanes and aryl trifluoroborates.…”

“…This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. was introduced to produce 18 F-labelled arenes with high A m s. [11][12][13][14][15][16][17][18][19][20] This transition metal-mediated synthesis pathway is based on the use of cyclotron-produced [ 18 F]F − . In 2011, Lee et al 11 reported the use of palladium complexes in 18 F-labelling reactions, but due to the moisture-sensitive nature of these complexes, a more convenient labelling method was still needed.…”