期刊
ACS OMEGA
卷 3, 期 7, 页码 7567-7579出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.8b00975
关键词
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资金
- faculty of Mathematics and Natural Sciences, University of Oslo
- Department of Chemistry, University of Oslo
- Norwegian Research Council [ES231553]
- NMS AS
- CORFO Innova Chile [14IEAT-28666]
- PositronPharma SA
- Kjemisk Institutt, UiO
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 [F-18]lansoprazole and N-methyl-[F-18]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 alpha-synuclein and beta-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.
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