Small Molecule Heterocycles: Design and Synthesis of Novel Fluorescent Benzothiazoles for Early Detection of...

Diagnostic agents capable of imaging β-amyloid (Aβ) plaques at prodromal stages could provide noninvasive tools to assess plaque burden and assist in determining efficacy of disease-modifying therapeutic interventions in vivo. To accomplish this goal, FDA approved ¹⁸F-incorporated tracers, such as Florbetapir, Flutemetamol, and Florbetaben may allow quantitative analysis of therapeutic efficacy of disease-modifying treatments that attenuate Aβ pathophysiology in vivo. Although promising, these tracers show high off-target binding. Importantly, current anti-amyloid therapy also targets diffuse amyloid plaques (included in revised NIAAA criteria for detecting AD) and other forms of amyloid plaques. Therefore, molecules capable of detecting both diffuse and fibrillar plaque pathology can potentially offer better quantitative tools for interrogating efficacy of anti-amyloid therapy. To achieve this goal, herein, we report synthesis and characterization of new small organic molecules: ((Z,E)-4-(2-(6-(2-Fluoroethoxy)benzo[d]thiazol-2-yl)vinyl)-N,N-dimethylaniline) 4, ((Z)-4-(2-(6-(2-(2-(3-Fluoropropoxy)ethoxy)ethoxy)benzo[d]thiazol-2-yl)vinyl)-N,N-dimethylaniline) 5a and ((E)-4-(2-(6-(2-(2-(3-Fluoropropoxy)ethoxy)ethoxy)benzo[d]thiazol-2-yl)vinyl)-N,N-dimethylaniline) 5b. We also report preliminary investigations on binding affinity in vitro. While 4 demonstrated a relatively higher affinity, both 5a and 5b showed moderate affinity for Aβ_1-42 aggregates in vitro. Furthermore, all 3 agents showed ability to detect Aβ fibrillar and diffuse plaque pathology in brain sections of APP/PS1 transgenic mice and post-mortem confirmed AD human brain tissue sections.