Abstract
BackgroundStatins 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. [18F]Atorvastatin, the 18F-labeled version of one of the most widely prescribed statins, may be a useful tool for statin-related research.Results[18F]Atorvastatin was synthesized via an optimized ruthenium-mediated late-stage 18F-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 [18F]atorvastatin in 19% ± 6% (d.c.) with a molar activity of 65 ± 32 GBq·μmol−1. Incubation of [18F]atorvastatin in human serum did not lead to decomposition. Furthermore, we have shown the ability of [18F]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 [18F]atorvastatin significantly accumulates in this tissue when compared to the healthy model.ConclusionsThe improved ruthenium-mediated 18F-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, [18F]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 [18F]atorvastatin may help to better understand the origin of off-target effects and potentially allow to distinguish between statin-resistant and non-resistant patients.
Highlights
Statins are lipid-lowering agents that inhibit cholesterol synthesis and are clinically used in the primary and secondary prevention of cardiovascular diseases
We report the 18F-labeling of atorvastatin (12), one of the most widely used statins in the prevention of cardiovascular risk factors and one of the bestselling drugs in pharmaceutical history [56]
The α,βunsaturated ketone 1 was combined with benzaldehydes 2 and 9, respectively, in the presence of triethylamine and the thiazolium bromide catalyst 3 to afford the corresponding 1,4-diketone intermediates 4 and 10, respectively
Summary
Statins are lipid-lowering agents that inhibit cholesterol synthesis and are clinically used in the primary and secondary prevention of cardiovascular diseases. Cardiovascular diseases represent one of the leading causes of death globally [1]. Atherosclerosis, a chronic inflammatory pathology characterized by deposition of plaques (a collection of fat, cholesterol, calcium, fibrin, and cellular waste products) in the walls of arteries, is the dominant cause of cardiovascular diseases [2]. Inhibition of HMG-CoA reductase with statins became an essential strategy for the primary prevention of atherosclerosis. Statins contain a dihydroxycarboxylic acid moiety that mimics and outcompetes the natural substrate molecule HMG-CoA, preventing its reduction to mevalonate and further cholesterol synthesis [27, 28] (Fig. 1a)
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