Identification of AV-1451 as a Weak, Nonselective Inhibitor of Monoamine Oxidase

Drake, Lindsey; Pham, Jonathan; Desmond, Timothy J.; Mossine, Andrew V.; Lee, So Jeong; Kilbourn, Michael R.; Koeppe, Robert A.; Brooks, Allen F.; Scott, Peter J. H.

doi:10.1021/acschemneuro.9b00326

Cited by 40 publications

(33 citation statements)

References 48 publications

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“…There is increasing evidence that Flortaucipir also has a binding affinity to monoamine oxidases (MAO) isoforms confirmed by enzyme inhibition assays, autoradiography and in vivo PET (32)(33)(34). A recent in vitro study showed a comparable binding strength of Flortaucipir to tau fibrils and MAO (35).…”

Section: Discussionmentioning

confidence: 99%

One-Stop Shop: ¹⁸F-Flortaucipir PET Differentiates Amyloid-Positive and -Negative Forms of Neurodegenerative Diseases

et al. 2020

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Section: Discussionmentioning

confidence: 99%

One-Stop Shop: ¹⁸F-Flortaucipir PET Differentiates Amyloid-Positive and -Negative Forms of Neurodegenerative Diseases

et al. 2020

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“…These data have generated considerable excitement for the utility of this signal, but they have illustrated shortcomings with regard to off-target binding. Notably, several of the first-generation ligands bind monoamine oxidase isoforms [28,77]. The substantial overlap in clinical presentation among primary tauopathies and other neurodegenerative syndromes further complicates the diagnostic utility of these agents.…”

Section: Strains In Diagnosis Of Tauopathiesmentioning

confidence: 99%

Tau strains shape disease

2021

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Tauopathies consist of over 25 different neurodegenerative diseases that include argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD). Tauopathies are defined by brain accumulation of microtubule-associated protein tau in fibrillar aggregates, whose prevalence strongly correlates with dementia. Dominant mutations in tau cause neurodegenerative diseases, and most increase its aggregation propensity. Pathogenesis of tauopathies may involve pathological tau conformers that serve as templates to recruit native protein into growing assemblies and also move between brain cells to cause disease progression, similar to prions. Prions adopt pathological conformations, termed “strains,” that stably propagate in living systems, and create unique patterns of neuropathology. Data from multiple laboratories now suggest that tau acts as a prion. It propagates unique strains indefinitely in cultured cells, and when these are inoculated into mouse models, they create defined neuropathological patterns, which establish a direct link between conformation and disease. In humans, distinct fibril structures are associated with different diseases, but causality has not been established as in mice. Cryo-EM structures of tau fibrils isolated from tauopathy brains reveal distinct fibril cores across disease. Interestingly, the conformation of the tau monomer unit within different fibril subtypes from the same patient appears relatively preserved. This is consistent with data that the tau monomer samples an ensemble of conformations that act as distinct pathologic templates in the formation of restricted numbers of strains. The propensity of a tau monomer to adopt distinct conformations appears to be linked to defined local motifs that expose different patterns of amyloidogenic amino acid sequences. The prion hypothesis, which predicts that protein structure dictates resultant disease, has proved particularly useful to understand the diversity of human tauopathies. The challenge now is to develop methods to rapidly classify patients according to the structure of the underlying pathological protein assemblies to achieve more accurate diagnosis and effective therapy.

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“…More selective PET radiotracers such as [ 18 F]THK5351 (Figure 1, 2 ) provided useful information on AD patients, but have recently been reported to have significant off‐target binding to monoamine oxidase (MAO B), reducing their potential use in AD diagnosis (Ng et al., 2017). Pyrrole derivatives such as [ 18 F]T807 (Figure 1, 3 ) also appear to show some off‐target MAO binding (e.g., Drake et al., 2019). Nevertheless, studies using [ 18 F]T807 and the related [ 18 F]RO6958948 (Figure 1, 4 ) continue for NFT imaging in AD (Honer et al., 2018).…”

Section: Introductionmentioning

confidence: 99%

Development and evaluation of [¹²⁵I]IPPI for Tau imaging in postmortem human Alzheimer's disease brain

Liang

Patel

Lam

et al. 2020

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Objective: Alzheimer's disease (AD) is a neurodegenerative disease characterized by aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) in the brain. The aim of this study was to develop and evaluate the effectiveness of a novel radioiodinated tracer, 6‐[125I]iodo‐3‐(1H‐pyrrolo[2,3‐c]pyridine‐1‐yl)isoquinoline ([125I]IPPI), for binding to Tau protein (Ki = 0.75 nM) in postmortem human brain (AD and cognitively normal (CN). Methods: Radiosynthesis of [125I]IPPI was carried out by radioiododestannylation and purified chromatographically. Computational modeling studies of IPPI and MK‐6240 binding on Tau fibril were evaluated. In vitro autoradiography studies were carried out with [3H]PIB for Aβ plaques and [125I]IPPI for Tau in AD and CN brains and evaluate drug effects. Results: [125I]IPPI was produced in >95% purity. Molecular modeling of IPPI revealed binding energies of IPPI (−7.8, −8.1, −8.2, −7.5 Kcal/mol) at the four sites were comparable to MK‐6240 (−8.7, −8.5, −8.3, −7.5 Kcal/mol). Ratio of average grey matter (GM) [125I]IPPI in AD versus CN was found to be 7.31 (p = .07) and AD GM/ white matter (WM) = 4.35 (p = .09). Ratio of average GM/WM [125I]IPPI in CN was 1.21. Binding of [125I]IPPI correlated with the presence of Tau, confirmed by anti‐Tau Dako A0024. Specifically bound [125I]IPPI to Tau in AD brains was displaced by MK‐6240 and IPPI (>90%). Monoamine oxidase inhibitors (MAO) inhibitors deprenyl and clorgyline effected [125I]IPPI binding at >1 µM concentrations. Conclusion: [125I]IPPI exhibited high binding in human AD frontal cortex and anterior cingulate and is a suitable radioiodinated ligand for Tau imaging.

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Identification of AV-1451 as a Weak, Nonselective Inhibitor of Monoamine Oxidase

Cited by 40 publications

References 48 publications

One-Stop Shop: ¹⁸F-Flortaucipir PET Differentiates Amyloid-Positive and -Negative Forms of Neurodegenerative Diseases

One-Stop Shop: ¹⁸F-Flortaucipir PET Differentiates Amyloid-Positive and -Negative Forms of Neurodegenerative Diseases

Tau strains shape disease

Development and evaluation of [¹²⁵I]IPPI for Tau imaging in postmortem human Alzheimer's disease brain

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Identification of AV-1451 as a Weak, Nonselective Inhibitor of Monoamine Oxidase

Cited by 40 publications

References 48 publications

One-Stop Shop: 18F-Flortaucipir PET Differentiates Amyloid-Positive and -Negative Forms of Neurodegenerative Diseases

One-Stop Shop: 18F-Flortaucipir PET Differentiates Amyloid-Positive and -Negative Forms of Neurodegenerative Diseases

Tau strains shape disease

Development and evaluation of [125I]IPPI for Tau imaging in postmortem human Alzheimer's disease brain

Contact Info

Product

Resources

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One-Stop Shop: ¹⁸F-Flortaucipir PET Differentiates Amyloid-Positive and -Negative Forms of Neurodegenerative Diseases

One-Stop Shop: ¹⁸F-Flortaucipir PET Differentiates Amyloid-Positive and -Negative Forms of Neurodegenerative Diseases

Development and evaluation of [¹²⁵I]IPPI for Tau imaging in postmortem human Alzheimer's disease brain