Deuterium Kinetic Isotope Effect Studies of a Potential <i>in Vivo</i> Metabolic Trapping Agent for Monoamine Oxidase B

Drake, Lindsey; Brooks, Allen F.; Mufarreh, Anthony; Pham, Jonathan; Koeppe, Robert A.; Shao, Xia; Scott, Peter J. H.; Kilbourn, Michael R.

doi:10.1021/acschemneuro.8b00219

Cited by 16 publications

(14 citation statements)

References 9 publications

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“…However, the technical challenges of irreversible inhibitors such as deprenyl hinder the accurate image analysis. Several reversible-binding inhibitors have been developed in recent years such as [ 11 C]Cou ( 170 , 219 ), [ 11 C]SL25.1188 ( 168 ), and [ 11 C]SMBT-1 ( 166 ). Harada et al showed a specific increased regional retention of [ 11 C]SMBT-1 in the cortical and hippocampal regions in patients with AD compared to healthy controls ( 166 ).…”

Section: Neuroinflammation Positron Emission Tomography Imagingmentioning

confidence: 99%

PET Imaging of Neuroinflammation in Alzheimer’s Disease

Zhou

Kong

et al. 2021

Front. Immunol.

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Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with Alzheimer’s disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer’s disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer’s disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable in vivo brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.

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Section: Neuroinflammation Positron Emission Tomography Imagingmentioning

confidence: 99%

PET Imaging of Neuroinflammation in Alzheimer’s Disease

Zhou

Kong

et al. 2021

Front. Immunol.

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“…There are exceptions to this concern, for example, if the radiotracer is trapped within the tissue and not distributed to plasma. This is exemplified with the radiotracer [ 11 C]Cou for which the polar metabolite is trapped in tissue (Drake et al, 2018).…”

Section: Not Knownmentioning

confidence: 99%

“…However, this radiotracer was not intended for human use due to the severe and largely irreversible toxic effects associated with pharmacological doses of MPTP. The MPTP analog 4-methyl-7-((1-[ 11 C]methyl-1,2,3,6tetrahydropyridin-4-yl)oxy)-2H-chromen-2-one ([ 11 C]Cou) was assessed in rhesus monkeys and found to be selectively metabolized by MAO-B; with the product of MAO-B oxidation and subsequent hydrolysis trapped in the brain (Drake et al, 2018). However, excessive trapping led to time activity curves that were insensitive to the relative density of MAO-B in the brain.…”

Section: Not Knownmentioning

confidence: 99%

“…However, excessive trapping led to time activity curves that were insensitive to the relative density of MAO-B in the brain. Two deuterium substituted analogs, ([ 11 C]Cou-d3 and ([ 11 C]Cou-d7) were created with the intention of reducing MAO-B metabolism further, by slowing down the hydrogen abstraction step, implicated as rate limiting in the MAO-B oxidation of MPTP, but the impact on time activity curves was fairly minimal, suggesting that these two analogs should not be developed further (Drake et al, 2018).…”

Section: Not Knownmentioning

confidence: 99%

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Development and Clinical Application of Positron Emission Tomography Imaging Agents for Monoamine Oxidase B

Meyer

Braga

2022

Front. Neurosci.

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Monoamine oxidase B (MAO-B) is a high-density protein in the brain mainly found on outer mitochondrial membranes, primarily in astroglia, but additionally in serotonergic neurons and in the substantia nigra in the midbrain. It is an enzyme that participates in the oxidative metabolism of important monoamines including dopamine, norepinephrine, benzylamine, and phenylethylamine. Elevated MAO-B density may be associated with astrogliosis and inhibiting MAO-B may reduce astrogliosis. MAO-B density is elevated in postmortem sampling of pathology for many neuropsychiatric diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and alcohol use disorder. Initial development of positron emission tomography (PET) imaging agents focused on analogs of [11C]L-deprenyl, with the most commonly applied being the deuterium substituted [11C]L-deprenyl-D2. This latter radiotracer was modeled with an irreversible trapping compartment reflecting its irreversible binding to MAO-B. Subsequently, [11C]SL25.1188, a reversible binding MAO-B radioligand with outstanding properties including high specific binding and excellent reversibility was developed. [11C]SL25.1188 PET was applied to discover a substantive elevation of MAO-B binding in the prefrontal cortex in major depressive disorder (MDD) with an effect size of more than 1.5. Longer duration of MDD was associated with greater MAO-B binding throughout most gray matter regions in the brain, suggesting progressive astrogliosis. Important applications of [11C]L-deprenyl-D2 PET are detecting a 40% loss in radiotracer accumulation in cigarette smokers, and substantial occupancy of novel therapeutics like EVT301 and sembragiline. Given the number of diseases with elevations of MAO-B density and astrogliosis, and the advance of [11C]SL25.1188, clinical applications of MAO-B imaging are still at an early stage.

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“…As an alternative strategy for radiotracer development toward MAOs, our program at the University of Michigan has investigated the use of metabolic trapping for imaging MAO enzymatic activity . In this approach, a substrate that is freely diffusible across the blood-brain barrier is designed such that the product of MAO oxidation is sufficiently polar to be retained within brain tissues at the sites of enzyme action (Figure ).…”

Section: Metabolic Trapping Mechanismmentioning

confidence: 99%

Classics in Neuroimaging: Development of PET Tracers for Imaging Monoamine Oxidases

Narayanaswami

Drake

Brooks

et al. 2019

ACS Chem. Neurosci.

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In this Viewpoint, we highlight the history of positron emission tomography (PET) radiotracer development to quantify changes in monoamine oxidase (MAO)-A and -B enzyme expression or activity. MAO-A and MAO-B are critical for understanding monoaminergic pathways in psychiatric addiction disorders, and more recently in neurodegenerative disorders with MAO-B expression in astrogliosis. Unique radiochemical innovations have been shown for neuroimaging of MAOs including the clinical translation of irreversible propargylamine-based suicide inhibitors, application of deuterium-substitution to slow down metabolism, development of trapped metabolite imaging agents, and unique 11 C-carbonylation chemistry toward novel high-affinity reversibly binding inhibitors.

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Deuterium Kinetic Isotope Effect Studies of a Potential in Vivo Metabolic Trapping Agent for Monoamine Oxidase B

Cited by 16 publications

References 9 publications

PET Imaging of Neuroinflammation in Alzheimer’s Disease

PET Imaging of Neuroinflammation in Alzheimer’s Disease

Development and Clinical Application of Positron Emission Tomography Imaging Agents for Monoamine Oxidase B

Classics in Neuroimaging: Development of PET Tracers for Imaging Monoamine Oxidases

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