Biocompatible fluorescent UV-VIS and NIR probes for the detection of ß-Amyloid Plaques and Tau fibrils

Ziele: As a promising new approach for the early diagnosis of Alzheimer's disease (AD), we evaluated novel fluorescent probes for the molecular imaging of amyloid-ß (Aß) deposits and fibrillar tau. The aim of our work was to assess their applicability as novel in vivo AD ligands by determining their target affinity and biocompatibility. Methode: The affinity of our novel UV-VIS fluorescent pyrazine and pyrimidine based bisstilbenes and NIR asymmetric hemicyanines to Aß deposits and tau fibrils were determined via histopathological staining of human AD brain slices and semiquantitative analysis of Aß1 – 42-binding dependent changes in fluorescence intensity in vitro. Potential cyto- or phototoxic effects of our probes were assessed by measuring the activity of intrinsic dehydrogenases of living cells via MTS assay, employing permanent and primary human cell lines. To clarify the role of intracellular ROS production in cytotoxic effects, intracellular ROS level were measured. The internalisation of the probes into cells was examined via confocal laser scanning microscopy. Ergebnis: While asymmetric hemicyanines were mainly selective towards tau, bisstilbenes stained Aß and tau, at which mainly 1 pyrimidine derivate achieved a two-fold (2.1 ± 0.4) increase in fluorescence intensity upon binding to Aß1 – 42-aggregates and IC50 values of 52 (Aß) and 2 nM (Tau).

Compared to MeX04 and ICG, especially pyrazines showed a better in vitro biocompatibility (cell viability on endothelial cells after 48h: 59.3 ± 0.5 to 86.0 ± 10.0%)

Cellular uptake of the probes was not associated with the impact on cell metabolism, but potential cytotoxic effects of selective pyrimidines and asymmetric hemicyanines were linked with an increased relative ROS production compared to untreated controls (1.97 ± 0.1; 2.0 ± 0.2). Schlussfolgerung: Our data suggest that our bisstilbenes and asymmetric hemicyanines are promising tools for the early AD in vivo diagnosis.

Korrespondierender Autor: Hölzer J

Jena University Hospital, Dept. of Experimental Radiology, Institute of Diagnostic and Interventional Radiology I, Erlanger Allee 101, 07747 Jena

E-Mail: [e-mail]

Alzheimer - Tau fibrils - Amyloid Plaques - Molecular Imaging - Fluorophores