Copper‐Mediated Aromatic Radiofluorination Revisited: Efficient Production of PET Tracers on a Preparative Scale

Abstract

Two novel methods for copper-mediated aromatic nucleophilic radiofluorination were recently reported. Evaluation of these methods reveals that, although both are efficient in small-scale experiments, they are inoperative for the production of positron emission tomography (PET) tracers. Since high base content turned out to be responsible for low radiochemical conversions, a "low base" protocol has been developed which affords (18)F-labeled arenes from diaryliodonium salts and aryl pinacol boronates in reasonable yields. Furthermore, implementation of our "minimalist" approach to the copper-mediated [(18)F]-fluorination of (mesityl)(aryl)iodonium salts allows the preparation of (18)F-labeled arenes in excellent RCCs. The novel radiofluorination method circumvents time-consuming azeotropic drying and avoids the utilization of base and other additives, such as cryptands. Furthermore, this procedure enables the production of clinically relevant PET tracers; [(18)F]FDA, 4-[(18)F]FPhe, and [(18)F]DAA1106 are obtained in good isolated radiochemical yields. Additionally, [(18)F]DAA1106 has been evaluated in a rat stroke model and demonstrates excellent potential for visualization of translocator protein 18 kDa overexpression associated with neuroinflammation after ischemic stroke.

Development of Customized [18F]Fluoride Elution Techniques for the Enhancement of Copper-Mediated Late-Stage Radiofluorination

“…However, the complicated reaction pathways involved in these new reactions have exposed limitations in the traditional method for handling cyclotron-produced [ 18 F]fluoride. For example, the Cu-mediated fluorination of organoboron compounds, originally developed by the Sanford group 20 and subsequently adapted for radiolabeling by Sanford and Scott 21 , Gouverneur 22, 23 , and Neumaier 24, 25 , has been used to prepare a range of radiofluorinated arenes in small-scale manual reactions. However, automation and scale-up to the Curie levels of [ 18 F]fluoride used in typical production of radiopharmaceuticals for clinical use have proven challenging 21, 24 .…”

“…K 2 CO 3 ) and cryptands (e.g. K 2.2.2 ) used for standard [ 18 F]fluoride processing result in suppressed radiochemical yields in this Cu-mediated [ 18 F]fluorination reaction, possibly due to the formation of unproductive copper adducts 24 . The presence of K 2 CO 3 and/or K 2.2.2 can also be detrimental to subsequent reactions and/or protecting group manipulations, as we have discovered in recent PET radiotracer development efforts 26 .…”

Synthesis of 5-[18F]Fluoro-α-methyl Tryptophan: New Trp Based PET Agents

“…Because the Cu reagent is base sensitive, the labeling yield was found to decrease when a larger volume of 18 F-TBAF solution was used for the reaction. This has been attributed to the higher amounts of residual tetrabutylammonium bicarbonate phase transfer catalyst present in larger volumes of 18 F-TBAF solution 39. Protection of the acidic indole -NH- was employed to increase the yield of the acid sensitive 18 F fluoride utilized in the labeling reaction.…”

Stereoselective radiosynthesis of l- and d-3-[18F]fluoro-α-methyltyrosine

“…However, an automated synthesis procedure of those methods still requires further optimization [17,18]. A method known for longer, which has the advantage of being easier to automate, is based on nucleophilic substitution with [ 18 F]fluoride on carbonyl-activated precursors, producing aromatic amino acids in a three-step, two-pot procedure.…”

“…A method known for longer, which has the advantage of being easier to automate, is based on nucleophilic substitution with [ 18 F]fluoride on carbonyl-activated precursors, producing aromatic amino acids in a three-step, two-pot procedure. For this, following reaction sequence was optimized: isotopic exchange, Baeyer-Villiger oxidation or decarbonylation reaction, and hydrolysis, as exemplified with 6-[ 18 [20] and 6-[ 18 F]fluoro-meta-L-tyrosine [21]. The aim of this work was to adapt this three step radiosynthetic approach, which particularly has the advantage of easy automation, to the preparation of L-and D-[ 18 F]FAMT, starting from [ 18 F]fluoride.…”