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

Abstract

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.

[18F]Atorvastatin Pharmacokinetics and Biodistribution in Healthy Female and Male Rats

“…Solvent gradient was as follows: 0–4 min, 90% A; 4–15 min, 90% A to 20% A; 15–25 min, 20% A to 5% A; 25–33 min, 5% A; 33–34 min, 5% A to 90% A; 34–35 min, 90% A; flow, 6 mL·min –1 ; R t ≈ 16 min. Finally, solid-phase extraction allowed for the exchange of solvents, and [ 18 F]atorvastatin was obtained in a physiological and injectable calcium acetate solution 15 (0.05 M pH 7.0) in <10% ethanol.…”

“… 16 , 17 Atorvastatin also seems to have a particular propensity for pleiotropic effects, which may be related to its lipophilicity. 18 − 20 Preliminary in vitro evaluations from our group 15 showed that [ 18 F]atorvastatin retains the specific binding to HMG-CoA reductase of the conventional drug and shows increased uptake in atherosclerotic plaques (approx. 2:1) with respect to healthy vascular tissues.…”

“…Replacing a stable fluorine atom by its radioisotope is not always straightforward, especially when it is located in electron-rich arenes that are not amenable to aromatic nucleophilic substitution, as in the case of statins. We previously reported that either Cu-mediated 18 F-fluorodeboronation or Ru- mediated 18 F-deoxyfluorination approaches can be used to synthesize a radiolabeled analog of atorvastatin, with the latter strategy providing far superior and reliable radiochemical yields (2% vs 20%). Atorvastatin is one of the most potent statins synthesized to date, being a standard treatment for primary and secondary prevention of cardiovascular diseases. , Atorvastatin also seems to have a particular propensity for pleiotropic effects, which may be related to its lipophilicity. − Preliminary in vitro evaluations from our group showed that [ 18 F]­atorvastatin retains the specific binding to HMG-CoA reductase of the conventional drug and shows increased uptake in atherosclerotic plaques (approx.…”

“…13 Replacing a stable fluorine atom by its radioisotope is not always straightforward, especially when it is located in electronrich arenes that are not amenable to aromatic nucleophilic substitution, as in the case of statins. We previously reported that either Cu-mediated 18 F-fluorodeboronation 14 or Rumediated 18 F-deoxyfluorination 15 approaches can be used to synthesize a radiolabeled analog of atorvastatin, with the latter strategy providing far superior and reliable radiochemical yields (2% vs 20%). Atorvastatin is one of the most potent statins synthesized to date, being a standard treatment for primary and secondary prevention of cardiovascular diseases.…”

The impact of statins on the course of a new coronavirus infection: myth or reality?

“…Основным эффектом статинов является снижение эндогенного синтеза холестерина путем ингибирования печеночной гидроксиметилглутарил (HMG) CoA-редуктазы, стадии, ограничивающей скорость мевалонатного пути производства холестерина [4]. Наряду с этим одним из наиболее важных эффектов терапии статинами является поддержание стабильности атеросклеротических бляшек [5].…”