Rational Design of Amyloid Binding Agents Based on the Molecular Rotor Motif

Abstract

Alzheimer's disease (AD) is characterized by a progressive loss of cognitive function and constitutes the most common and fatal neurodegenerative disorder.[1] Genetic and clinical evidence supports the hypothesis that accumulation of amyloid deposits in the brain plays an important role in the pathology of the disease. This event is associated with perturbations of biological functions in the surrounding tissue leading to neuronal cell death, thus contributing to the disease process. The deposits are comprised primarily of amyloid (Aβ) peptides, a 39-43 amino acid sequence that self aggregates into a fibrillar β-pleated sheet motif. While the exact three-dimensional structure of the aggregated Aβ peptides is not known, a model structure that sustains the property of aggregation has been proposed. [2] This creates opportunities for in vivo imaging of amyloid deposits that can not only help evaluate the time course and evolution of the disease, but can also allow the timely monitoring of therapeutic treatments. [3] Keywords amyloid peptides; fluorescent probes; imaging agents; molecular rotors Historically, Congo Red (CR) and Thioflavin T (ThT) have provided the starting point for the visualization of amyloid plaques and are still commonly employed in post mortem histological analyses (Figure 1).[4] However, due to their charge these probes are unsuitable for in vivo applications. [5] To address this issue, several laboratories developed probes with noncharged, lipophilic (log P = 0.1-3.5) and low-molecular weight chemical structures (MW <650) that facilitate crossing of the blood-brain barrier.[6] Further functionalization of these compounds with radionuclides led to a new generation of in vivo diagnostic reagents (Figure 1) that target plaques and related structures for imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT Figure 1 reveals that the majority of these probes contain an electrondonor unit in conjugation with an electron acceptor (D-π-A motif). This motif is a typical feature in molecular rotors, a family of fluorescent probes known to form twisted intramolecular charge-transfer (TICT) complexes in the excited state producing a fluorescence quantum yield that is dependent on the surrounding environment.[11] Following photoexcitation, this motif has the unique ability to relax either via fluorescence emission or via an internal nonradiative molecular rotation. This internal rotation occurs around the σ-bonds that connect the electron-rich π-system with the donor and acceptor groups, and can be modified by altering the chemical structure and microenvironment of the probe.[12] Hindrance of the internal molecular rotation of the probe by increasing the surrounding media rigidity, or by reducing the available free volume needed for relaxation, leads to a decrease in the nonradiative decay rate and consequently an increase in fluorescence. In contrast, relaxation proceeds mainly via nonradiative pathways in environments of low viscosity or of hi...

Apparent Shear Sensitivity of Molecular Rotors in Various Solvents

“…Compounds 3 − 6 were synthesized by our group as reported elsewhere [22]. The chemical structures are found in Fig.…”

Vapochromic features of new luminogens based on julolidine-containing styrene copolymers

“…14,15 It is worth noting that amongst C-C and C=C bonds, recent reports suggest that C-C rotation is too slow to quench the fluorescence, hence the cis-trans isomerization of the C=C bond is the major nonradiative decay channel in these systems. 23,58,59 Furthermore, quantum chemical computations indicated that in the excited state rotation around the connecting C-C bond is subject to a higher barrier than that found for the ground state, thus fluorescence loss is not completely rationalizable through rotation around this bond. However, calculation…”

Detection of Amyloid β Signature in the Lens and Its Correlation in the Brain to Aid in the Diagnosis of Alzheimer’s Disease

“…Bioavailability and toxicity/phototoxicity studies in addition to in vitro fluorescence characterization of the ointment have already been demonstrated. 26 …”

“…The study demonstrated the safety and effectiveness of the FLES technique in predicting clinical diagnosis. 26 In this study, we conducted a clinical trial on 40 participants (20 probable AD and 20 HV) and compared the results obtained by FLES in the eye with that obtained by amyloid florbetapir F18 PET imaging in the brain.…”