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  • The absence of an observable time dependence


    The absence of an observable time dependence of kobs on inhibitor concentration for fauc 3 with AChE and compounds 1, 3 and 4 with BuChE parallels a similar absence of time dependence for some related fluoro ketones with AChE. Nair et al. found that trifluoromethyl acetophenones with small meta-substituents such as methyl, ethyl, amino or nitro groups did not inhibit AChE in a time-dependent manner but appeared to be reversible inhibitors. They suggested that the larger meta-substituents in compounds 1 and 2 can undergo London dispersion interactions in the cholinesterase active site that increase the affinity of trifluoroacetophenones for the enzyme. Such an increase in affinity adds to their appeal as potential imaging agents. Selective labeling of the target macromolecule is an important goal in neuroimaging. Because of their unique character as tetrahedral transition state analogs of cholinesterases, trifluoroacetophenones should have very high selectivity for AChE and BuChE in the central nervous system. This high selectivity is based on the high affinity of these compounds for the AChE and BuChE active sites, and it is enhanced by the slow dissociation rate constants that several trifluoroacetophenones exhibit with these enzymes. Slow dissociation implies that these compounds will persist in complex with their target molecules during the washout typical of PET imaging analysis. These desirable properties are especially evident in m-tert-butyltrifluoroacetophenone (2), which exhibits both high affinities (low Kis) for the cholinesterase active sites and a low dissociation rate constant kd. These features promise to ensure more selective binding of 18F labeled acetophenone with cholinesterases associated with AD pathology for PET detection.
    Conclusion Two m-substituted trifluoroacetophenones, 1 and 2, have been prepared in a reaction with potential to generate 18F radioligands for the neuroimaging of cholinesterases associated with AD neuropathology. The precursor molecules of the possible radioligands, m-substituted chlorodifluoroacetophenones 3 and 4, are readily prepared and sufficiently stable to be made in advance and stored for extended periods without chemical degradation. Kinetic evaluations of the trifluoroacetophenones 1 and 2 indicate they bind with high affinity to both AChE and BuChE. The ability to rapidly introduce 19F by converting 3 to 1 and 4 to 2 indicates that these molecules have potential for development as radioligands for the neuroimaging of cholinesterases and the localization of these enzymes with AD pathology. The present work provides the basis for future studies directed towards incorporation of 18F into these molecules for PET imaging of cholinesterases in the brain.
    Materials and methods
    Acknowledgments Canadian Institutes of Health Research (Frederick Banting and Charles Best Canada Graduate Scholarships, MOP-82798, RNS-117795, MOP-119343), Killam Trusts, Dalhousie Medical Research Foundation Irene MacDonald Sobey Chair in Curative Approaches to Alzheimer’s Disease, Ms. Sadie Macleod through the Dalhousie Medical Research Foundation Adopt-A-Researcher Program, the Committee on Research and Publications, Mount Saint Vincent University, the Brain Repair Centre, Nova Scotia Health Research Fund, Nova Scotia Health Research Foundation (MED-MAT-2011-7512), Faculty and Department of Medicine of Dalhousie University, Innovacorp and Dalhousie Medical Research Foundation.
    Introduction During the last decade, several studies have shown that cholinesterase (ChE) activities can be significantly altered following exposure to a large set of different chemicals and complex mixtures (Garcia et al., 2000; Sánchez-Hernandez, 2001; Kopecka et al., 2004; Barillet et al., 2007; Li, 2008, Ramos et al., 2012; Nunes et al., 2014). Cholinesterases are enzymes of particular importance, since some of them are involved in the regulation of key features of the nervous system; acethylcholinesterase (AChE), for instance, is responsible for the physiological degradation by hydrolysis of the neurotransmitter acetylcholine in cholinergic synapses of most organisms. Its inhibition results in severe neurotransmission impairment, due to the accumulation of the neurotransmitter acetylcholine at synaptic clefts, leading to nervous overstimulation and ultimately death (Pope et al., 2005). Exposure to environmental anticholinesterasic compounds (e.g. organophosphate and carbamate pesticides, which act specifically on the active site of the enzyme; Nunes, 2011) has been traditionally assessed by quantifying AChE activity of non-target organisms (Yi et al., 2006; Guimarães et al., 2007). However, exposure to other chemicals, including detergents, specific metals, and complex mixtures of pollutants (Labrot et al., 1996, Payne et al., 1996, Frasco et al., 2005, Nunes et al., 2005, Ramos et al., 2012, de Lima et al., 2013) seemed also to result in cholinesterasic inhibition in laboratory animals as well as in feral sentinel or indicator species (Gagnaire et al., 2008, Oliveira et al., 2012).