Thioesters for the <i>in vitro</i> evaluation of agents to image brain cholinesterases

Macdonald, Ian R.; Jollymore, Courtney; Reid, G. Andrew; Pottie, Ian R.; Martin, Earl; Darvesh, Sultan

doi:10.3109/14756366.2011.647008

Cited by 3 publications

(10 citation statements)

References 35 publications

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“…Changes in the activity and location of AChE are linked to neurodegenerative diseases. For example, AChE is overexpressed in patients with Alzheimer’s disease . The major therapeutics to treat mild to moderate Alzheimer’s disease act by inhibition of brain AChE .…”

Section: Resultsmentioning

confidence: 99%

“…For example, AChE is overexpressed in patients with Alzheimer's disease. 49 The major therapeutics to treat mild to moderate Alzheimer's disease act by inhibition of brain AChE. 49 In vivo and real-time monitoring of AChE activity could facilitate early diagnosis and treatment of neurodegenerative diseases and the rational design of drugs.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…49 The major therapeutics to treat mild to moderate Alzheimer's disease act by inhibition of brain AChE. 49 In vivo and real-time monitoring of AChE activity could facilitate early diagnosis and treatment of neurodegenerative diseases and the rational design of drugs. We spiked 0.3 mM ACh into rat brain tissue homogenate and monitored the emf of the ISE.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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In Situ Sensing of the Neurotransmitter Acetylcholine in a Dynamic Range of 1 nM to 1 mM

et al. 2018

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The neurotransmitter acetylcholine (ACh) plays a key role in the pathophysiology of brain disorders such as Alzheimer's disease. Understanding the dynamics of ACh concentration changes and kinetics of ACh degradation in the living brain is crucial to unravel the pathophysiology of such diseases and the rational design of therapeutics. In this work, an electrochemical sensor capable of dynamic, label-free, selective, and in situ detection of ACh in a range of 1 nM to 1 mM (with temporal resolution of less than one second) was developed. The sensor was employed for the direct detection of ACh in artificial cerebrospinal fluid and rat brain homogenate, without any prior separation steps. A potentiometric receptor-doped ion-selective electrode (ISE) with selectivity for ACh was designed by taking advantage of the positive charge of ACh. The dynamic range, limit of detection (LOD), and the selectivity of the sensor were optimized stepwise by (i) screening of hydrophobic biomimetic calixarenes to identify receptors that strongly bind to ACh based on shape-selective multitopic recognition, (ii) doping of the ISE sensing membrane with an ACh-binding hydrophobic calixarene to enable selective detection of ACh in complex matrices, (iii) utilizing a hydrophilic calixarene in the inner filling solution of the ISE to buffer the concentration of ACh and, thereby, lower the LOD of the sensor, and (iv) introducing a surface treatment step prior to the measurement by placing the sensor for ∼1 min in a solution of a hydrophilic calixarene to lower the LOD of the sensor even further.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

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In Situ Sensing of the Neurotransmitter Acetylcholine in a Dynamic Range of 1 nM to 1 mM

et al. 2018

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“…In a previous study, Macdonald et al. 49 evaluated a series of N -methylpiperidinyl thioesters for staining of AChE or BChE in human brain tissue using the Karnovsky-Roots (KR) histochemical method 50 . It was found that thioesters could be employed for the histochemical detection of the enzyme activity associated with normal neural structures in brain tissues and that this staining could be used for comparison with in vivo images generated by analogous radiolabelled molecules.…”

Section: Introductionmentioning

confidence: 99%

“…Thioesters allowed for the direct evaluation of specificity and determination of enzyme kinetic parameters with AChE or BChE. They also allowed for the evaluation of the interaction of these compounds with ChEs in human and mouse AD brain tissues using the KR method, as done previously 49 . Esters were evaluated for specificity and determination of enzyme kinetic parameters with AChE or BChE using competition studies with a spectrophotometric method, as described previously 51–53 .…”

Section: Introductionmentioning

confidence: 99%

A method for the efficient evaluation of substrate-based cholinesterase imaging probes for Alzheimer’s disease

Darvesh

Banfield

Dufour

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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Cholinesterase (ChE) enzymes have been identified as diagnostic markers for Alzheimer disease (AD). Substrate-based probes have been synthesised to detect ChEs but they have not detected changes in ChE distribution associated with AD pathology. Probes are typically screened using spectrophotometric methods with pure enzyme for specificity and kinetics. However, the biochemical properties of ChEs associated with AD pathology are altered. The present work was undertaken to determine whether the Karnovsky-Roots (KR) histochemical method could be used to evaluate probes at the site of pathology. Thirty thioesters and esters were synthesised and evaluated using enzyme kinetic and KR methods. Spectrophotometric methods demonstrated all thioesters were ChE substrates, yet only a few provided staining in the brain with the KR method. Esters were ChE substrates with interactions with brain ChEs. These results suggest that the KR method may provide an efficient means to screen compounds as probes for imaging AD-associated ChEs.

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Vardanyan¹

2017

Piperidine-Based Drug Discovery

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Thioesters for the in vitro evaluation of agents to image brain cholinesterases

Cited by 3 publications

References 35 publications

In Situ Sensing of the Neurotransmitter Acetylcholine in a Dynamic Range of 1 nM to 1 mM

In Situ Sensing of the Neurotransmitter Acetylcholine in a Dynamic Range of 1 nM to 1 mM

A method for the efficient evaluation of substrate-based cholinesterase imaging probes for Alzheimer’s disease

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