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| Home > Publications database > Synthesis of an F-18-labelled NO-synthase inhibitor |
| Conference Presentation (Plenary/Keynote) | FZJ-2016-07743 |
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2015
Abstract: Objectives: Nitric oxide (NO), an important signalling molecule in the human body, is synthesised by three isoforms of NO-synthase (NOS) from the amino acid L-arginine. Overproduction of NO by neuronal NOS has been associated with neurodegenerative disorders. Therefore, developing small molecules for selective inhibition of nNOS over related isoforms (iNOS and eNOS) is therapeutically desirable and of great interest for decoding neurodestructive key factors [1]. Suitable 18F-labelled NOS-Inhibitors should allow the investigation of NOS-function by molecular imaging. Potentially, the highly selective nNOS Inhibitor 6-((3-((3-fluorophenylethylamino)methyl)phenoxy)methyl)-4-methyl-pyridine-2-amine [2] is a suitable target for labelling with n.c.a. [18F]fluoride in addition to the established iNOS inhibitor 6-(2-[18F]fluoropropyl)-4-methylpyridine-2-amine [3].Methods: Based on tert-butyl-(3-iodophenylethyl)carbamate the corresponding iodoniumylide precursor was formed [4]. The activated aromatic system was labelled with n.c.a. [18F]fluoride and converted via reductive amination followed by microwave assisted displacement of the protecting groups to the desired nNOS inhibitor. For the development of a simplified late-stage labelling procedure the corresponding brominated, Boc- and pyrrole-protected compound was synthesised, which was converted via borylation into the boronic ester precursor. This compound was labelled authentically by copper(II) mediated n.c.a. 18F-fluorination [5]. Further developments enabled the one-pot synthesis by adapting the [18F]fluoride activation to the radiolabelling step leading to ready-to-automate conditions. Furthermore, an automated one-pot procedure for the synthesis of the iNOS-Inhibitor was examined after stability tests and kinetic studies.Results: The n.c.a. 18F-fluorination of the iodoniumylide precursor proceeded efficiently and regioselective in 79 % radiochemical yield (RCY). The following built-up synthesis led to the desired nNOS inhibitor in 15 % RCY. First attempts of the late-stage copper(II) mediated n.c.a. 18F-fluorination led to similar conversions. The labelling procedure was reduced to a simplified one-pot synthesis. Conclusion: Finally, there are now potential and isoform selective radiotracers for both inducible and neuronal NO-synthases with high molar activities for further evaluations and preclinical studies.References: [1] Mukherjee P. et al. (2014), Chem. Soc. Rev., 43, 6814-6838.[2] Jing Q. et al. (2013), Bioorg. Med. Chem., 21, 5323. [3] Zhou D. et al. (2009), J. Med. Chem., 52, 2443.[4] Cardinale J. et al. (2013), Tetr. Lett., 54, 2067.[5] Tredwell M. et al. (2014), Angew. Chem. Int. Ed., 53, 7751.
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