© 2016, Springer-Verlag Berlin Heidelberg. Detection of amyloid-β (Aβ) aggregates in the brain is essential for an early diagnosis and for tracing the evolution of Alzheimer’s disease. Positron emission tomography is the most commonly used technique for Aβ detection, but fluorescence imaging is a promising alternative. For their in vivo application, fluorescent Aβ markers should emit in the near-infrared region and present strong binding affinities for Aβ aggregates. The dithiophene-based NIAD-4 dye and its derivatives NIAD-11 and NIAD-16 are within the most interesting Aβ markers as they fulfill these two criteria. In this contribution, the photophysical properties of these compounds as well as their binding to amyloid-β fibrils have been studied with a combination of computational techniques (TDDFT and MS-CASPT2 calculations, AIMD simulations and fit-induced docking calculations). Modifications on the NIAD-4 skeleton have little effects on the ground and excited state properties of the dye as well as on the feasibility of the most probable non-radiative deactivation pathways. However, they tune the absorption and emission wavelengths and affect significantly the blood–brain barrier (BBB) permeability and binding site preference toward Aβ fibrils. A red-shifting of the emission wavelength is achieved by enlarging the π-system in NIAD-11 and by increasing the charge transfer in NIAD-16, the effect of the former being significantly larger in gas phase. However, the larger solvatochromic effect observed for NIAD-16 leads to similar emission wavelengths in water solution for the two dyes. Overall, the variation of the charge transfer extent of the transition seems to be more appropriate at least in this case, since it has a smaller effect on the BBB permeability and binding site preference of the new dye with respect to the original NIAD-4.
|Journal||Theoretical Chemistry Accounts|
|Publication status||Published - 1 Aug 2016|
- Charge transfer
- Conical intersection
- Induced fit docking
- Intersystem crossing