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

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. [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. CONCLUSIONS: The 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

Leuckart-Wallach Route Toward Isocyanides and Some Applications

Isocyanide-based multicomponent reactions (IMCR) are among the most important chemical reactions to efficiently generate molecular diversity and have found widespread use in industry and academia. Generally, isocyanides are synthesized in 1-2 steps starting from primary amines. Here, we provide experimental detail on an alternative approach toward formamides and, thus, isocyanides via the Leuckart-Wallach reaction in an improved variation. The resulting >50 synthesized and characterized formamides are useful starting materials for IMCR, as well as other chemistries. The advantage of using the Leuckart-Wallach pathway to formamides and isocyanides is the lower price, on average, of the starting materials, as well as their differential and complementary structural diversity, as compared to the primary amine pathway

CCDC 1060616: Experimental Crystal Structure Determination

Related Article: Constantinos G. Neochoritis, Tryfon Zarganes-Tzitzikas, Silvia Stotani, Adrian Dömling, Eberhardt Herdtweck, Kareem Khoury, Alexander Dömling|2015|ACS Comb. Sci.|17|493|doi:10.1021/acscombsci.5b00066,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

CCDC 1060614: Experimental Crystal Structure Determination

Related Article: Constantinos G. Neochoritis, Tryfon Zarganes-Tzitzikas, Silvia Stotani, Adrian Dömling, Eberhardt Herdtweck, Kareem Khoury, Alexander Dömling|2015|ACS Comb. Sci.|17|493|doi:10.1021/acscombsci.5b00066,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

CCDC 1060615: Experimental Crystal Structure Determination

Related Article: Constantinos G. Neochoritis, Tryfon Zarganes-Tzitzikas, Silvia Stotani, Adrian Dömling, Eberhardt Herdtweck, Kareem Khoury, Alexander Dömling|2015|ACS Comb. Sci.|17|493|doi:10.1021/acscombsci.5b00066,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

CCDC 986845: Experimental Crystal Structure Determination

Related Article: Tryfon Zarganes-Tzitzikas, Pravin Patil, Kareem Khoury, Eberhardt Herdtweck, Alexander Dömling|2015|Eur.J.Org.Chem.|2015|51|doi:10.1002/ejoc.20140340

CCDC 1453287: Experimental Crystal Structure Determination

Related Article: Rudrakshula Madhavachary, Tryfon Zarganes-Tzitzikas, Pravin Patil, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, Alexander Dömling|2018|ACS Comb. Sci.|20|192|doi:10.1021/acscombsci.7b00145,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

CCDC 1453288: Experimental Crystal Structure Determination

Related Article: Rudrakshula Madhavachary, Tryfon Zarganes-Tzitzikas, Pravin Patil, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, Alexander Dömling|2018|ACS Comb. Sci.|20|192|doi:10.1021/acscombsci.7b00145,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

CCDC 986844: Experimental Crystal Structure Determination

Related Article: Tryfon Zarganes-Tzitzikas, Pravin Patil, Kareem Khoury, Eberhardt Herdtweck, Alexander Dömling|2015|Eur.J.Org.Chem.|2015|51|doi:10.1002/ejoc.20140340

CCDC 1869941: Experimental Crystal Structure Determination

Related Article: Constantinos Neochoritis, Ehsan Ghonchepour, Maryam Kazemi Miraki, Tryfon Zarganes-Tzitzikas, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, Alexander Doemling|2018|Eur.J.Org.Chem.|2018|50|doi:10.1002/ejoc.20180158