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  • br Experimental section br Results and discussion


    Experimental section
    Results and discussion
    Acknowledgements This work was financially supported by Recruitment Program of Global Experts, and the Director Foundation of XTIPC, CAS, Grant No. 2015RC011. This work was also financially supported by Natural Science Foundation of Xinjiang, China, Grant No. 2016D01A073. This work was also financially supported by the Central Asian Drug Discovery and Development Center of Chinese Academy of Sciences.
    Introduction Impairment in the brain CARIPORIDE (ACh) neurotransmission has long been postulated as a downstream process in the cognitive deficit related to Alzheimer's disease (AD). Indeed, despite the progresses achieved in understanding the multifactorial causes and histopathological hallmarks of AD, only a few drugs have been approved, most of which are acetylcholinesterase (AChE) inhibitors (e.g., rivastigmine, galantamine, and donepezil), for the symptomatic relief of mild to moderate AD (Geldenhuys and Darvesh, 2015). The cholinergic deficit in the brain leading to neurodegenerative disorders, as assessed by the diminution of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities in neocortex and hippocampus constitutes an important neurochemical change mainly related to impairment in learning, memory, behavior and emotional responses (Roberson and Harrell, 1997). The neurotransmitter acetylcholine (ACh) is mainly hydrolyzed by AChE in the synaptic cleft of the cholinergic neurons, but at higher concentrations is also hydrolyzed by butyrylcholinesterase (BChE), which is also localized the CNS glial cells and neurons, where it contribute to regulate cholinergic neurotransmission (Greig et al., 2005, Darvesh et al., 2012, de Candia et al., 2017). In addition to being a drug target for at least the symptomatic treatment of AD, AChE is an attractive diagnostic target for measuring the cholinergic activity in normal and degenerative brain syndromes (Colombres et al., 2004, McGeer and McGeer, 2003, Kumar and Calache, 1991). Indeed, AChE inhibitors have found application as radioligands for measuring cholinergic activity in the AD early diagnosis. Among several N-benzyl piperidine-containing inhibitors showing AChE inhibition potency in the low nanomolar range (IC50=8–10nM), only a few compounds displayed AChE specific binding affinity in in vivo studies (Choe et al., 2000, Brown-Proctor et al., 1996, De Vos et al., 2000, Lee et al., 2006, Lee et al., 2007b, Lee et al., 2007a, Funaki et al., 2003). Among them, a series of N-benzyl piperidine derivatives of the tricyclic 5,7-dihydro-6H-isoxazolo[4,5-f]indol-6-one moiety (CP-118,954 and CP-126,998; Fig. 1) exhibited (sub)nanomolar affinities and high selectivity for AChE (Villalobos et al., 1995). In 2002, Musachio et al. (2002) reported the synthesis of a radioligand containing a lactam benzisoxazole analog (CP-126,998; IC50=0.48nM), which was successfully radiolabeled with carbon-11. Subsequently, Choe's group prepared a CP-118,954 radiolabeled with 18F or 125I (Lee et al., 2004, Lee et al., 2007b, Lee et al., 2007a, Ryu et al., 2005). The 11C- and 18F-labeled forms (and not the 125I-labeled one) proved to be selectively accumulated in the striatum, which is an AChE-rich region. It has been demonstrated that fluorination of aromatic CH may enhance the binding affinity of a ligand toward a targeted enzyme's binding site (Purser et al., 2008). In the case of AChE inhibitors bearing the N-benzyl moiety, such as donepezil, the meta-fluorinated analog proved to be a remarkably more potent inhibitor in vitro (Lee et al., 2000). In addition, the X-ray crystallographic study of AChE supported the development of AChE inhibitors through identification of two distinct ligand binding sites, a catalytic anionic site and a peripheral anionic site, and interaction between halogen and Trp278 in a peripheral anionic site (Harel et al., 2008, Mostofi et al., 2015). Nonetheless, the meta-F-substituted donepezil has not been explored as a radioligand for measuring AChE activity, due to the limitation of the 18F-labeling methods at the meta-position of the aromatic ring. For the same reason, CP-118,954, which showed higher in vitro binding affinity than donepezil, 18F-labeling has been achieved at only the ortho- and para-positions of the N-benzyl moiety. Recently, diaryliodonium salts have been shown to be useful precursors for direct nucleophilic 18F-labeling into both electron-rich and electron-deficient aromatic rings (Pike et al., 1999, Lee et al., 2007b, Lee et al., 2007a, Lee et al., 2009, Lee et al., 2011). Furthermore, pharynx methodology provides aromatic [18F]fluorination into the less reactive meta-position, such as meta-[18F]fluorobenzaldehyde (Moon et al., 2009, Basuli et al., 2011, Chun et al., 2011). In addition, the readily available aryl boron reagents (Tredwell et al., 2014, Mossine et al., 2015) and the spirocyclic hypervalent iodine (III) complex (Rotstein et al., 2014) have been successfully applied for radiofluorination of non-activated aryl fragment.