Preparation of No‐Carrier‐Added 6‐[¹⁸F]Fluoro‐l‐tryptophan via Cu‐Mediated Radiofluorination

Abstract

18F‐Labeled aromatic amino acids exhibit great potential for diagnostic applications using positron emission tomography. However, the introduction of 18F into aromatic compounds remains challenging, and novel fluorination methods facilitating easy access to 18F‐labeled arenes are highly sought after. In recent years, novel metal‐mediated fluorination methods have been reported and transferred into radiochemistry. Based on Cu‐mediated radiofluorination, a two‐step synthesis of no‐carrier‐added (n.c.a.) 6‐[18F]fluoro‐l‐tryptophan was developed. 6‐[18F]Fluoro‐l‐tryptophan was synthesized with an overall radochemical yield of 16 ± 4% within 110 min and a specific activity of 280 GBq µmol–1. The radiochemical purity was more than 99 %. The developed method allowed access to radiofluorinated tryptophan derivatives in high radiochemical yields and opens new ways to provide radiofluorinated amino acids. Furthermore, the reaction conditions were optimized to facilitate automation.

Alcohol‐Enhanced Cu‐Mediated Radiofluorination

“…The introduction of O-a nd N-containing substitu- 11)f rom the corresponding unprotected precursors, albeit in lower RCCs of up to 10 and 21 %, respectively. [14] Figure 3. Radiolabeling of indoles is of significant interest given their importance as cycloxygenase-2, cannabinoid receptor type 2, b-adrenoreceptor,a nd 5-hydroxytryptamine receptor type 3l igands.…”

Effect of Pyridine Addition on the Efficiency of Copper‐Mediated Radiofluorination of Aryl Pinacol Boronates

“…Reactions performed using either DMA or NMP (Table S3) gave inferior RCC compared to DMF. Despite DMA being the solvent of choice for copper‐mediated fluorinations of arylBPin aromatic substrates in the presence of TEAHC,, DMF was found to be the best for our conditions using Cs 2 CO 3 /K 222 as a solubilizing agent.…”

“…Particularly, the implementation of copper‐mediated Chan‐Lam type C−F cross coupling reaction for radiofluorination of pinacol esters of arylboronic acids (arylBPin) in the presence of Cu(OTf) 2 (py) 4 (Scheme , A) has attracted much attention as an effective route for introducing 18 F‐label into electron‐neutral, ‐rich and ‐poor arenes. The method tolerates wide array of functional groups, enabling it to be applied to various aromatic systems, including clinically relevant radiotracers . However, implementation into production stage revealed the problem of copper catalyst stability in basic conditions.…”

“…In order to resolve this issue the “low base” protocol based on the elution of the [ 18 F]fluoride from the ion‐exchange resin using minimal amounts of base ‐ 0.06 mg, 0.43 μmol of K 2 CO 3 , instead of usually used 2.8‐3.5 mg, 20–25 μmol, was developed, enabling high‐yield synthesis under production conditions with suitable equipment. Additionally, using solution of tetraethylammonium bicarbonate (1‐2 μmol/mL) in methanol in lieu of inorganic base has led to high elution efficiency of [ 18 F]fluoride trapped on the anion‐exchange resin leading to good radiochemical conversion (RCC) ,. Further improvement of this methodology via addition of alcohols as co‐solvents led to substantially increased radiolabeling yields when applied to various boronic‐ and stannyl substrates and simplified process of automation …”

Microwave‐Assisted Rapid One‐Pot Synthesis of Fused and Non‐Fused Indoles and 5‐[18F]Fluoroindoles from Phenylazocarboxylates

“…A major advance in direct 18 F‐fluorination of aromatics was made through copper‐catalyzed reactions of aryl boronic acids and boronates . Although this reaction type at first gave only low yields of 18 F‐substituted indoles– and tryptophans, a remarkable breakthrough for this methodology was recently achieved by Zischler et al . through the addition of alcohols to the reaction mixture (Scheme A and B).…”