Image-Guided Development of Heterocyclic Sulfoxides as Ligands for Tau Neurofibrillary Tangles: From First-in-Man to Second-Generation Ligands
| العنوان: | Image-Guided Development of Heterocyclic Sulfoxides as Ligands for Tau Neurofibrillary Tangles: From First-in-Man to Second-Generation Ligands |
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| المؤلفون: | Henry Engler, Vasko Kramer, Horacio Amaral, Mona M. Spilhaug, Alexander Hoepping, Patrick J. Riss, Rodrigo Kuljs, Eduardo Savio, René Smits, Tania Pardo, Waqas Rafique |
| المصدر: | ACS Omega ACS Omega, Vol 3, Iss 7, Pp 7567-7579 (2018) |
| بيانات النشر: | American Chemical Society, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, medicine.diagnostic_test, Dementia with Lewy bodies, General Chemical Engineering, Lansoprazole, Sulfoxide, General Chemistry, Protein aggregation, Fibril, medicine.disease, Article, lcsh:Chemistry, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, lcsh:QD1-999, chemistry, Neuroimaging, Positron emission tomography, medicine, Biophysics, Protein folding, 030217 neurology & neurosurgery, medicine.drug |
| الوصف: | Positron emission tomography (PET) imaging of misfolded protein aggregates that form in neurodegenerative processes of the brain is key to providing a robust marker for improved diagnosis and evaluation of treatments. We report the development of advanced radiotracer candidates based on the sulfoxide scaffold found in proton pump inhibitors (lansoprazole, prevacid) with inherent affinity to neurofibrillary tangles in Alzheimer’s disease and related disorders (e.g., dementia with Lewy bodies and the frontotemporal degeneration syndrome). First-in-man results obtained with [18F]lansoprazole and N-methyl-[18F]lansoprazole were used to guide the design of a set of 24 novel molecules with suitable properties for neuroimaging with PET. Compounds were synthesized and characterized pharmacologically, and the binding affinity of the compounds to synthetic human tau-441 fibrils was determined. Selectivity of binding was assessed using α-synuclein and β-amyloid fibrils to address the key misfolded proteins of relevance in dementia. To complete the pharmacokinetic profiling in vitro, plasma protein binding and lipophilicity were investigated. Highly potent and selective new radiotracer candidates were identified for further study. |
| اللغة: | English |
| تدمد: | 2470-1343 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::319c0a7169dbda16d4d63b9c046d2d88 http://europepmc.org/articles/PMC6068598 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....319c0a7169dbda16d4d63b9c046d2d88 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 24701343 |
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