Radioiodinated Tau Imaging Agent III Molecular Modeling, Synthesis, and Evaluation of a New Tau Imaging Agent, [125I]ISAS in Post-Mortem Human Alzheimer’s Disease Brain

Molecules, Journal Year: 2024, Volume and Issue: 29(14), P. 3308 - 3308

Published: July 13, 2024

Using a molecular modeling approach for Tau-binding sites, we modified our previously reported imaging agent, [125I]INFT, the potential improvement of binding properties to Tau in an Alzheimer’s disease (AD) brain. Two new derivatives, namely [125I]ISAS and [125I]NIPZ, were designed, where energies at site 1 −7.4 −6.0 kcal/mole, respectively, compared [125I]INFT (−7.6 kcal/mole). The radiosynthesis [125I]NIPZ was carried out by using iodine-125 purified chromatographically achieve >90% purity. In vitro affinities (IC50) as follows: INFT = 7.3 × 10−8 M; ISAS 4.7 NIPZ > 10−6 M. gray matter (GM) correlated with presence AD brain, confirmed anti-Tau immunohistochemistry. did not bind Tau, similar levels observed GM white (WM). Four radiotracers rank order found be [125I]IPPI >>> GM/WM ratios 7.74 4.86 3.62 >> 1.24. predictive value Chimera–AutoDock structurally related compounds sites (measured energy) good. A energy less than −7 kcal/mole is necessary −8 will more suitable developing agents.

Language: Английский

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Proteomic insights into early-stage Alzheimer’s disease: Identifying key neuronal proteins impacted by amyloid beta oligomers in an in vitro model

Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

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

Molecules, Journal Year: 2023, Volume and Issue: 28(15), P. 5769 - 5769

Published: July 31, 2023

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 novel radioiodinated tracer, 4-[125I]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)pyridine ([125I]INFT), for binding postmortem human AD brain. Radiosynthesis [125I]INFT was carried out using electrophilic destannylation by iodine-125 purified chromatographically. Computational modeling INFT on fibril compared with IPPI. In vitro, autoradiography studies were conducted cognitively normal (CN) brains. produced >95% purity. Molecular revealed comparable energies IPPI at site-1 an affinity IC50 = 7.3 × 10-8 M. Binding correlated presence brain, confirmed anti-Tau immunohistochemistry. The ratio average grey matter (GM) versus CN found be 5.9, GM/white (WM) 2.5. Specifically bound brains displaced (>90%). Monoamine oxidase inhibitor deprenyl had no effect clorgyline little binding. less lipophilic imaging agent AD.

Language: Английский

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Chromenone: An emerging scaffold in anti-Alzheimer drug discovery

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 111, P. 129912 - 129912

Published: July 30, 2024

Language: Английский

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