Synthesis of a Potent Aminopyridine-Based nNOS-Inhibitor by Two Recent No-Carrier-Added (18)F-Labelling Methods.
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 (18)F-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 (18)F-labelled in no-carrier-added (n.c.a.) form. For preparation of the (18)F-labelled nNOS-Inhibitor [(18)F]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. [(18)F]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" (18)F-labelling procedure a corresponding boronic ester precursor was synthesized and successfully used in a newer, copper(II) mediated n.c.a. (18)F-fluoro-deboroniation reaction, achieving the same total RCY. Thus, both methods proved comparatively suited to provide the highly selective NOS-inhibitor [(18)F]10 as probe for preclinical in vivo studies.
Institut für Neurowissenschaften und Medizin, INM-5: Nuklearchemie, Forschungszentrum Jülich, 52425 Jülich, Germany. ch.drerup@fz-juelich.de.
Christian
C
Drerup
Institut für Neurowissenschaften und Medizin, INM-5: Nuklearchemie, Forschungszentrum Jülich, 52425 Jülich, Germany. j.ermert@fz-juelich.de.
Johannes
J
Ermert
Institut für Neurowissenschaften und Medizin, INM-5: Nuklearchemie, Forschungszentrum Jülich, 52425 Jülich, Germany. h.h.coenen@fz-juelich.de.
Heinz H
HH
Coenen
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D007553:Isotope Labeling; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000631:Aminopyridines; D004791:Enzyme Inhibitors; D005462:Fluorine Radioisotopes; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I
copper-mediated labelling; iodonium ylides; nNOS-inhibitor; radiofluorination; radiopharmaceuticals