Site‐Specific Deoxyfluorination of Small Peptides with [<sup>18</sup>F]Fluoride

Rickmeier, Jens; Ritter, Tobias

doi:10.1002/ange.201807983

Cited by 12 publications

(9 citation statements)

References 33 publications

(17 reference statements)

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“…This optimized method boosted and simplified the 18 F-deoxyfluorination technique by avoiding the addition of salt additives, skipping any need for washing the trapped [ 18 F]fluoride, circumventing time-consuming azeotropic drying (with the consequent radioactivity losses by natural decay, evaporation, and unspecific adsorption to the reactor surface) and the use of different solvent mixtures for the various steps of the process (elution and 18 F-fluorination). The amount of Ru-coordinated precursor 8 was also reduced in relation to the previously reported 18 F-deoxyfluorination works (2.5 μmol vs. 5.0 μmol) [58][59][60]. During the optimization work, it became evident that some procedure deviations such as air bubbling instead of stirring, absence of mechanical mixing, increased solvent volumes, larger reaction vials, or flat-shaped bottom ones can decrease the final 18 F-deoxyfluorination yield.…”

Section: Synthesis Of Precursors and 18 F-fluorination Strategysupporting

confidence: 51%

“…This widely clinically prescribed statin has evident benefits in cardiovascular disease prevention and may play a role in other conditions that still require further elucidation. The adjustments used in this work for the Ru-mediated 18 F-deoxyfluorination strategy proved to be an improvement compared to the previously reported procedures [58][59][60], including halving the initial labeling precursor amount, avoiding the use of different solvent mixtures and salt additives, and omitting [ 18 F]fluoride washing and solvent removal procedures. This, together with the simplicity of the process, the tolerance to a variety of solvents (including aqueous solutions), and the low reaction volumes used, might result in the Rumediated deoxyfluorination strategy being suitable for implementation in emerging techniques such as microfluidics-lab-on-a-chip radiochemistry or microdroplet radiosynthesizers.…”

Section: Discussionmentioning

confidence: 91%

“…For the radiofluorination of atorvastatin, the benzyl ether pyrrole intermediate 6 was synthesized and subsequently converted to the corresponding phenol 7 by palladium on carbon (Pd/C)-catalyzed hydrogenolysis (Scheme 2). Coordination of 7 to ruthenium (II) decreases its π-electron density, providing 8, and activates the precursor towards radiodeoxyfluorination [58][59][60].…”

Section: Synthesis Of Precursors and 18 F-fluorination Strategymentioning

confidence: 99%

“…As expected, most of the tested additives have a negative effect on the 18 F-deoxyfluorination yield. The use of bis(trimethylneopentylammonium) oxalate [58][59][60] gave the best overall yields of [ 18 F]11. This addition still decreases the 18 F-deoxyfluorination conversion by approximately 10% when compared to the experiments without an eluent additive.…”

Section: Synthesis Of Precursors and 18 F-fluorination Strategymentioning

confidence: 99%

“…However, in the case of atorvastatin, the 18 F-fluorination of electron-rich arenes is a classical struggle in radiochemistry and has challenges associated with synthesis automation [57]. The fluorine-containing aromatic ring within the atorvastatin structure is electron-rich, and therefore, we use the ruthenium-mediated radiodeoxyfluorination strategy [58][59][60] to synthesize [ 18 F]atorvastatin ([ 18 F]12). This radiotracer may have the potential to become an attractive tool for statin-related research, enabling the understanding of cellular and subcellular mechanisms, the identification of off-target activity and, ultimately, allowing to select between statin-resistant and non-resistant patients for targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

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[18F]Atorvastatin: synthesis of a potential molecular imaging tool for the assessment of statin-related mechanisms of action

et al. 2020

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Background: Statins are lipid-lowering agents that inhibit cholesterol synthesis and are clinically used in the primary and secondary prevention of cardiovascular diseases. However, a considerable group of patients does not respond to statin treatment, and the reason for this is still not completely understood. [ 18 F]Atorvastatin, the 18 Flabeled version of one of the most widely prescribed statins, may be a useful tool for statin-related research. Results: [ 18 F]Atorvastatin was synthesized via an optimized ruthenium-mediated late-stage 18 F-deoxyfluorination. The defluoro-hydroxy precursor was produced via Paal-Knorr pyrrole synthesis and was followed by coordination of the phenol to a ruthenium complex, affording the labeling precursor in approximately 10% overall yield. Optimization and automation of the labeling procedure reliably yielded an injectable solution of [ 18 F]atorvastatin in 19% ± 6% (d.c.) with a molar activity of 65 ± 32 GBq·μmol −1 . Incubation of [ 18 F]atorvastatin in human serum did not lead to decomposition. Furthermore, we have shown the ability of [ 18 F]atorvastatin to cross the hepatic cell membrane to the cytosolic and microsomal fractions where HMG-CoA reductase is known to be highly expressed. Blocking assays using rat liver sections confirmed the specific binding to HMG-CoA reductase. Autoradiography on rat aorta stimulated to develop atherosclerotic plaques revealed that [ 18 F]atorvastatin significantly accumulates in this tissue when compared to the healthy model. Conclusions: The improved ruthenium-mediated 18 F-deoxyfluorination procedure overcomes previous hurdles such as the addition of salt additives, the drying steps, or the use of different solvent mixtures at different phases of the process, which increases its practical use, and may allow faster translation to clinical settings. Based on tissue uptake evaluations, [ 18 F]atorvastatin showed the potential to be used as a tool for the understanding of the mechanism of action of statins. Further knowledge of the in vivo biodistribution of [ 18 F]atorvastatin may help to better understand the origin of off-target effects and potentially allow to distinguish between statin-resistant and non-resistant patients.

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Section: Synthesis Of Precursors and 18 F-fluorination Strategysupporting

confidence: 51%

Section: Discussionmentioning

confidence: 91%

Section: Synthesis Of Precursors and 18 F-fluorination Strategymentioning

confidence: 99%

Section: Synthesis Of Precursors and 18 F-fluorination Strategymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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[18F]Atorvastatin: synthesis of a potential molecular imaging tool for the assessment of statin-related mechanisms of action

et al. 2020

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Site‐Selective Trifluoromethylation Reactions of Oligopeptides

Guerrero

Correa

2020

Asian J Org Chem

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Site-selective chemical modifications that target proteinogenic amino acid residues complement the methods entailing genetic manipulation, thereby allowing straightforward and rapid access to engineered proteins. The incorporation of the trifluoromethyl group into amino acids within a peptide sequence results in relevant peptidomimetics with unique biomedicinal properties. As a result, the last decade has witnessed the development of a powerful set of protocols toward the selective trifluoromethylation of smallto-medium size peptides and proteins in a late-stage fashion. This minireview seeks to highlight those particularly compelling cases published in the last years.[a] I.

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