Abstract
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.
Highlights
Nitric oxide (NO) is an important signalling molecule and a unique mediator of a variety of physiological and pathological processes in the human body [1]
2 and deprotonation of 4, the lithiated compound 5 was quenched with trimethylsilylchloride (TMSCl), needed for an unambiguous identification of the desired radiolabelled nNOS-tracer
The pathway from an iodonium ylide precursor allowed for an efficient nucleophilic
Summary
Nitric oxide (NO) is an important signalling molecule and a unique mediator of a variety of physiological and pathological processes in the human body [1]. NO is synthesized endogenously from L-arginine by the enzyme nitric oxide synthase (NOS) existing in three isoforms [2]. There are two low-output isoforms of the NOS family, producing NO constitutively: the neuronal (nNOS) and the endothelial (eNOS) isoform. The nNOS generates NO as a neurotransmitter in brain and peripheral nerve cells, whereas eNOS derived NO is involved in the regulation of blood pressure, primarily in vascular endothelial cells. The third, inducible (iNOS) isoform is induced by various inflammatory stimuli (e.g., endotoxin) and plays a crucial role in the immune system’s defence against pathogens and tumour cells. The iNOS can generate high amounts of NO up to μM concentrations and for a prolonged period of time such as for hours or days [3]
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