Comparison of Monoamine Oxidase-A, Aβ Plaques, Tau, and Translocator Protein Levels in Postmortem Human Alzheimer’s Disease Brain

Syed, Amina; Liang, Christopher; Patel, Krystal; Mondal, Rommani; Kamalia, Vallabhi M.; Moran, Taylor R.; Ahmed, Sibtain

doi:10.3390/ijms241310808

Cited by 8 publications

(6 citation statements)

References 58 publications

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“…Iodine-124 is a long-half-life PET radioisotope that has been used for imaging various CNS targets [26]. We have successfully radiolabeled small molecules with iodine-124 for imaging Aβ plaques [15,28].…”

Section: Discussionmentioning

confidence: 99%

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[125I]IPC-Lecanemab: Synthesis and Evaluation of Aβ-Plaque-Binding Antibody and Comparison with Small-Molecule [18F]Flotaza and [125I]IBETA in Postmortem Human Alzheimer’s Disease

Liang,

Paclibar,

Gonzaga

et al. 2024

Neurology International

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Therapeutic antibodies for reducing Aβ plaque load in Alzheimer’s disease (AD) is currently making rapid progress. The diagnostic imaging of Aβ plaque load in AD has been underway and is now used in clinical studies. Here, we report our preliminary findings on imaging a therapeutic antibody, Lecanemab, in a postmortem AD brain anterior cingulate. [125I]5-iodo-3-pyridinecarboxamido-Lecanemab ([125I]IPC-Lecanemab) was prepared by coupling N-succinimidyl-5-([125I]iodo)-3-pyridinecarboxylate with Lecanemab in modest yields. The distinct binding of [125I]IPC-Lecanemab to Aβ-rich regions in postmortem human AD brains was higher in grey matter (GM) containing Aβ plaques compared to white matter (WM) (GM/WM was 1.6). Anti-Aβ immunostaining was correlated with [125I]IPC-Lecanemab regional binding in the postmortem AD human brains. [125I]IPC-Lecanemab binding was consistent with the binding of Aβ small molecules, [18F]flotaza and [125I]IBETA, in the same subjects. [18F]Flotaza and [125I]IBETA, however, exhibited significantly higher GM/WM ratios (>20) compared to [125I]IPC-Lecanemab. Our results suggest that radiolabeled [125I]IPC-Lecanemab retains the ability to bind to Aβ in human AD and may therefore be useful as a PET imaging radiotracer when labeled as [124I]IPC-Lecanemab. The ability to directly visualize in vivo a promising therapeutic antibody for AD may be useful in treatment planning and dosing and could be complimentary to small-molecule diagnostic imaging to assess outcomes of therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

“…Based on these values, the Braak scores of the CN subjects were I-II, and those of the AD subjects were V-VI. Further details of these subjects have been previously reported [26].…”

Section: Human Tissuementioning

confidence: 99%

[125I]IPC-Lecanemab: Synthesis and Evaluation of Aβ-Plaque-Binding Antibody and Comparison with Small-Molecule [18F]Flotaza and [125I]IBETA in Postmortem Human Alzheimer’s Disease

Liang,

Paclibar,

Gonzaga

et al. 2024

Neurology International

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“…Although an NMDA ion channel blocker, memantine, is used therapeutically in advanced AD [ 20 , 36 , 57 ], our findings suggest that the diagnostic and therapeutic targeting of the ion channel, glutamate site and glycine site may be appropriate in further refining and complementing the diagnosis and treatment of mild to severe AD [ 58 , 59 ]. Radiolabeling approaches with carbon-11, fluorine-18 and iodine-123/124 could be pursued to demonstrate their feasibility.…”

Section: Discussionmentioning

confidence: 99%

Glutamate’s Effects on the N-Methyl-D-Aspartate (NMDA) Receptor Ion Channel in Alzheimer’s Disease Brain: Challenges for PET Radiotracer Development for Imaging the NMDA Ion Channel

Shah,

Ghazaryan,

Gonzaga

et al. 2023

Molecules

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In an effort to further understand the challenges facing in vivo imaging probe development for the N-methyl-D-aspartate (NMDA) receptor ion channel, we have evaluated the effect of glutamate on the Alzheimer’s disease (AD) brain. Human post-mortem AD brain slices of the frontal cortex and anterior cingulate were incubated with [3H]MK-801 and adjacent sections were tested for Aβ and Tau. The binding of [3H]MK-801 was measured in the absence and presence of glutamate and glycine. Increased [3H]MK-801 binding in AD brains was observed at baseline and in the presence of glutamate, indicating a significant increase (>100%) in glutamate-induced NMDA ion channel activity in AD brains compared to cognitively normal brains. The glycine effect was lower, suggesting a decrease of the co-agonist effect of glutamate and glycine in the AD brain. Our preliminary findings suggest that the targeting of the NMDA ion channel as well as the glutamate site may be appropriate in the diagnosis and treatment of AD. However, the low baseline levels of [3H]MK-801 binding in the frontal cortex and anterior cingulate in the absence of glutamate and glycine indicate significant hurdles for in vivo imaging probe development and validation.

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“…Both [ 125 I]INFT and [ 125 I]IPPI provide reasonable GM/WM ratios in AD postmortem brains, although ratios with [ 125 I]IPPI are higher [14,15]. The availability of radioiodinated Tau imaging agents will enable in vitro evaluation of drugs [23,24].…”

Section: Discussionmentioning

confidence: 99%

[125I]INFT: Synthesis and Evaluation of a New Imaging Agent for Tau Protein in Post-Mortem Human Alzheimer’s Disease Brain

2023

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Aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) is a neuropathological feature in Alzheimer’s disease (AD). This study aimed to develop and evaluate the effectiveness of a novel radioiodinated tracer, 4-[125I]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)pyridine ([125I]INFT), for binding to Tau protein in postmortem human AD brain. Radiosynthesis of [125I]INFT was carried out using electrophilic destannylation by iodine-125 and purified chromatographically. Computational modeling of INFT binding on Tau fibril was compared with IPPI. In vitro, autoradiography studies were conducted with [125I]INFT for Tau in AD and cognitively normal (CN) brains. [125I]INFT was produced in >95% purity. Molecular modeling of INFT revealed comparable binding energies to IPPI at site-1 of the Tau fibril with an affinity of IC50 = 7.3 × 10−8 M. Binding of [125I]INFT correlated with the presence of Tau in the AD brain, confirmed by anti-Tau immunohistochemistry. The ratio of average grey matter (GM) [125I]INFT in AD versus CN was found to be 5.9, and AD GM/white matter (WM) = 2.5. Specifically bound [125I]INFT to Tau in AD brains was displaced by IPPI (>90%). Monoamine oxidase inhibitor deprenyl had no effect and clorgyline had little effect on [125I]INFT binding. [125I]INFT is a less lipophilic imaging agent for Tau in AD.

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Comparison of Monoamine Oxidase-A, Aβ Plaques, Tau, and Translocator Protein Levels in Postmortem Human Alzheimer’s Disease Brain

Cited by 8 publications

References 58 publications

[125I]IPC-Lecanemab: Synthesis and Evaluation of Aβ-Plaque-Binding Antibody and Comparison with Small-Molecule [18F]Flotaza and [125I]IBETA in Postmortem Human Alzheimer’s Disease

[125I]IPC-Lecanemab: Synthesis and Evaluation of Aβ-Plaque-Binding Antibody and Comparison with Small-Molecule [18F]Flotaza and [125I]IBETA in Postmortem Human Alzheimer’s Disease

Glutamate’s Effects on the N-Methyl-D-Aspartate (NMDA) Receptor Ion Channel in Alzheimer’s Disease Brain: Challenges for PET Radiotracer Development for Imaging the NMDA Ion Channel

[125I]INFT: Synthesis and Evaluation of a New Imaging Agent for Tau Protein in Post-Mortem Human Alzheimer’s Disease Brain

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