This title appears in the Scientific Report :
2015
Please use the identifier:
http://hdl.handle.net/2128/9189 in citations.
Synthese $^{18}$F-markierter NO-Synthase-Inhibitoren
Synthese $^{18}$F-markierter NO-Synthase-Inhibitoren
Nitric oxide (NO), an important signalling molecule, is synthesized from L-arginine by threeisoforms of NO-synthase (NOS. Its overproduction has been associated with neurodegenerativedisorders. Therefore, developing selective inhibitors of iNOS or nNOS is of greatinterest for decoding neurodestructi...
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Personal Name(s): | Drerup, Christian (Corresponding author) |
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Contributing Institute: |
Nuklearchemie; INM-5 |
Imprint: |
Jülich
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag
2015
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Physical Description: |
239 p. |
Dissertation Note: |
Dissertation, Universität zu Köln, 2015 |
Document Type: |
Report Book Dissertation / PhD Thesis |
Research Program: |
Neuroimaging |
Series Title: |
Berichte des Forschungszentrums Jülich
4390 |
Subject (ZB): | |
Link: |
OpenAccess OpenAccess |
Publikationsportal JuSER |
Nitric oxide (NO), an important signalling molecule, is synthesized from L-arginine by threeisoforms of NO-synthase (NOS. Its overproduction has been associated with neurodegenerativedisorders. Therefore, developing selective inhibitors of iNOS or nNOS is of greatinterest for decoding neurodestructive key factors. Suitable $^{18}$F-labelled analogues wouldallow for investigation of the NOS-function by molecular in vivo imaging with positronemission-tomography. Potentially, the highly selective nNOS inhibitor 6-((3-((3-fluorophenylethylamino)methyl)phenoxy)methyl)-4-methyl-pyridine-2-amine (1) is a suitable compoundfor labelling with no-carrier-added (n.c.a.) [$^{18}$F]fluoride, complementing the established iNOSinhibitor 6-(2-[$^{18}$F]fluoropropyl)-4-methylpyridine-2-amine [Abb.] Presently the radioorganic syntheses of n.c.a. $^{18}$F-labelled products are practically limited to nucleophilic procedures. Based on cyclic voltammetric measurements an electrochemical synthesis of n.c.a. $\textit{N}$-[$^{18}$F]fluorobis(trifluoromethylsulfonyl)imide (Tf$_{2}$N-[$^{18}$F]F) was attempted. The following conversion of the electrosynthetic product with an activated arene led to an $^{18}$F-labelled derivative. In this early developmental stage, a production of an n.c.a. electrophilic $^{18}$F-fluorinating reagent from [$^{18}$F]fluoride appears probable. For the effective labelling of NOS-inhibitors, however more sophisticated labelling methods had to be chosen. With regard to the nNOS-Inhibitor [$^{18}$F]1 a built-up radiosynthesis based on a iodonium ylide 2 as precursor was attempted. The activated aromatic system was efficiently and regionselectively 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 15 % RCY. Alternatively, for a simplified late-stage $^{18}$F-labelling procedure the corresponding boronic ester precursor 3 was synthesized and labelled starting by novel copper(II) mediated n.c.a. $^{18}$F-fluorination and led to the same RCY. After optimizing the radiolabelling procedure of the established iNOS inhibitor 6-(2-[$^{18}$F]Fluorpropyl)-4-methylpyridin-2-amin, now there are two highly selective NOS-inhibitors available for preclinical $\textit{in vivo}$ evaluation studies. |