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11C and 18FRadiolabeling of Tetra- and Pentathiophenes as PET-ligands for Amyloid Protein Aggregates
Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden..
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2016 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 7, no 4, 368-373 p.Article in journal (Refereed) Published
Abstract [en]

Three oligothiophenes were evaluated as PET tracers for the study of local and systemic amyloidosis ex vivo using tissue from patients with amyloid deposits and in vivo using healthy animals and PET-CT. The ex vivo binding studies revealed that all three labeled compounds bound specifically to human amyloid deposits. Specific binding was found in the heart, kidney, liver and spleen. To verify the specificity of the oligothiophenes towards amyloid deposits, tissue sections with amyloid pathology were stained using the fluorescence exhibited by the compounds and evaluated with multiphoton microscopy. Furthermore, in vivo rat and monkey PET-CT studies showed very low uptake in the brain, pancreas and heart of the healthy animals indicating low non-specific binding to healthy tissue. The biological evaluations indicated that this is a promising group of compounds for the visualization of systemic and localized amyloidosis.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016. Vol. 7, no 4, 368-373 p.
National Category
Chemical Sciences Cell Biology
Identifiers
URN: urn:nbn:se:liu:diva-122273DOI: 10.1021/acsmedchemlett.5b00309ISI: 000374436700007OAI: oai:DiVA.org:liu-122273DiVA: diva2:865139
Note

Funding agencies:  Swedish Research Council; Swedish Foundation for Strategic Research; LiU-Neuro; Ehrling-Persson Foundation; Goran-Gustafsson Foundation; ERC Starting Independent Researcher grant (Project: MUMID)

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Available from: 2015-10-27 Created: 2015-10-27 Last updated: 2016-05-12Bibliographically approved
In thesis
1. Asymmetric Oligothiophenes: Chemical Evolution of Multimodal Amyloid Ligands
Open this publication in new window or tab >>Asymmetric Oligothiophenes: Chemical Evolution of Multimodal Amyloid Ligands
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Luminescent conjugated polymers (LCPs) and luminescent conjugated oligothiophenes (LCOs) can be used as molecular probes to study diseases associated with protein aggregation. The conventionally used dyes to study and detect protein aggregates, denoted amyloid, have been Congo red (CR) and Thioflavin T (ThT). In contrast to these amyloid ligands, LCOs offer the possibility to detect aggregated proteinaceous species occurring at earlier stages of amyloid formation as well as to distinguish different morphotypes of protein aggregates. The interaction between the LCOs and the protein deposits can be studied by fluorescence spectroscopy and microscopy both in vitro and ex vivo. In this thesis we report the development of multimodal asymmetric LCOs that can be utilized with two novel techniques, Surface Plasmon Resonance (SPR) and Positron Emission Tomography (PET), to study the interaction between LCO and amyloid fibrils in real time. With SPR, we have been able to determine binding affinities between LCO and amyloid, and with PET we have shown that radiolabelled LCOs can be used as a non-invasive method to study amyloid deposits in vivo. In addition, by alteration of the backbone (change of thiophene units), and of adding different side chains functionalities, we have shown that the properties of the amyloid ligands have a huge impact of the binding to different stages or forms of protein aggregates. By making asymmetrical LCOs, which can be attached to a surface, we also foresee a methodology that will offer the possibility to create a sensitive and selective detection method, and maybe lead to a lab-on-a-chip-application.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 67 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1692
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-122278 (URN)10.3384/diss.diva-122278 (DOI)978-91-7685-987-2 (print) (ISBN)
Public defence
2015-11-20, Planck, Fysikhuset, Campus Valla, Linköping, 10:15 (Swedish)
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Available from: 2015-10-27 Created: 2015-10-27 Last updated: 2015-11-02Bibliographically approved

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Johansson, Leif B. G.Bäck, MarcusSjölander, DanielHammarström, PerNilsson, K. Peter R.
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