Synthesis of a Potent Aminopyridine-Based nNOS-Inhibitor by Two Recent No-Carrier-Added $^{18}$F-Labelling Methods

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Drerup, Christian ; Ermert, Johannes ; Coenen, Heinrich Hubert (2016)
  • Publisher: MDPI75390
  • Journal: (issn: 1420-3049)
  • Related identifiers: doi: 10.3390/molecules21091160
  • Subject: radiopharmaceuticals | copper-mediated labelling | nNOS-inhibitor | radiofluorination | Organic chemistry | QD241-441 | iodonium ylides
    • ddc: ddc:540

Nitric oxide (NO), an important multifunctional signaling molecule, is produced by three isoforms of NO-synthase (NOS) and has been associated with neurodegenerative disorders. Selective inhibitors of the subtypes iNOS (inducible) or nNOS (neuronal) are of great interest for decoding neurodestructive key factors, and 18F-labelled analogues would allow investigating the NOS-function by molecular imaging with positron emission tomography. Especially, the highly selective nNOS inhibitor 6-((3-((3-fluorophenethylamino)methyl)phenoxy)methyl)-4-methylpyridin-2-amine (10) lends itself as suitable compound to be 18F-labelled in no-carrier-added (n.c.a.) form. For preparation of the 18F-labelled nNOS-Inhibitor [18F]10 a “build-up” radiosynthesis was developed based on a corresponding iodonium ylide as labelling precursor. The such activated phenethyl group of the compound was efficiently and regioselectively labelled with n.c.a. [18F]fluoride in 79% radiochemical yield (RCY). After conversion by reductive amination and microwave assisted displacement of the protecting groups, the desired nNOS-inhibitor was obtained in about 15% total RCY. Alternatively, for a simplified “late-stage” 18F-labelling procedure a corresponding boronic ester precursor was synthesized and successfully used in a newer, copper(II) mediated n.c.a. 18F-fluoro-deboroniation reaction, achieving the same total RCY. Thus, both methods proved comparatively suited to provide the highly selective NOS-inhibitor [18F]10 as probe for preclinical in vivo studies.
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