Targeting butyrylcholinesterase for preclinical single photon emission computed tomography (SPECT) imaging of Alzheimer's disease

Abstract

IntroductionDiagnosis of Alzheimer's disease (AD) in vivo, by molecular imaging of amyloid or tau, is constrained because similar changes can be found in brains of cognitively normal individuals. Butyrylcholinesterase (BChE), which becomes associated with these structures in AD, could elevate the accuracy of AD diagnosis by focusing on BChE pathology in the cerebral cortex, a region of scant BChE activity in healthy brain.MethodsN-methylpiperidin-4-yl 4-[123I]iodobenzoate, a BChE radiotracer, was injected intravenously into B6SJL-Tg(APPSwFlLon, PSEN1∗M146 L∗L286 V) 6799Vas/Mmjax (5XFAD) mice and their wild-type (WT) counterparts for comparative single photon emission computed tomography (SPECT) studies. SPECT, computed tomography (CT), and magnetic resonance imaging (MRI) enabled comparison of whole brain and regional retention of the BChE radiotracer in both mouse strains.ResultsRetention of the BChE radiotracer was consistently higher in the 5XFAD mouse than in WT, and differences were particularly evident in the cerebral cortex.DiscussionCerebral cortical BChE imaging with SPECT can distinguish 5XFAD mouse model from the WT counterpart.

Preventive effect of N-stearoylethanolamine on memory disorders, blood and brain biochemical parameters in rats with experimental scopolamine-induced cognitive impairment

“…Recent findings indicated that some of NAEs are competitive (anandamide) and non-competitive (oleoylethanolamine and palmitoylethanolamine) inhibitors of plasma butyrylcholinesterase (BuChE) [29]. Changes in the level and activity of this enzyme were indicated in the pathogenesis of diseases associated with cognitive disorders (AD, multiple sclerosis) [30,31].…”

Cholinesterases in normal and Alzheimer's disease primary olfactory gyrus

“…If so, supplementing current clinical signs and symptoms with targeted molecular imaging of olfactory structures, such as the POG, could serve as noninvasive biomarkers of early AD. Preferential involvement of BChE with AD pathology elsewhere suggests that such targeted imaging of BChE in the POG may be particularly sensitive at detecting and distinguishing early AD changes .…”

Synthesis and Initial Characterization of a Reversible, Selective 18F-Labeled Radiotracer for Human Butyrylcholinesterase

“…However, advanced progression of AD involves a rapid decrease of AChE levels in the brain of9 0 %, which is accompanied in later-stage AD by elevated BChE expression. AChE and BChE exhibit very different localisations, biochemical features, and physiological functions [11]; however, BChE can take over the hydrolytic function of AChE [12][13][14][15][16]. These findings make BChE an attractive target for the development of more potent drugs for combatting AD [8][9][10].…”

“…[ 123 I]MP4Bz was applied in single-photon emission computed tomography (SPECT) studies, in which it was possible to distinguish cerebral cortical BChE activity in wild-type mice from an AD model [16]. This represents an important proof of concept, which demonstrates that BChE can indeed serve as a promising biomarker in AD diagnostics [15,21].…”

“…Irreversible inhibitor-derived tracers can have a complex mechanism of enzyme inactivation and it is often complicated to accurately determine in vivo kinetics and distribution [ 24 , 26 ]. Examples of substrate-type tracers specific for BChE include N -methylpiperidin-4-yl 4-[ 123 I]iodobenzoate ([ 123 I]MP4Bz), N -[ 18 F]fluoroethylpiperidin-4-ylmethyl butyrate, and 1-[ 11 C]-methyl-4-piperidinyl n -butyrate ([ 11 C]MP4B) [ 16 , 27 , 28 ]. [ 11 C]MP4B enters the brain, but no enhanced activity can be seen in regions where BChE-associated plaques typically show up in AD, which is likely the same for N -[ 18 F]fluoroethylpiperidin-4-ylmethyl butyrate.…”