Synthesis and Evaluation of Thiophene-Based PI-2620 Analogues Reveal Structure Dependent Aβ/Tau Selectivity in Alzheimer's disease

Sammanfattning

The diagnostic term Alzheimer's disease was coined more than a century ago to describe a neurodegenerative disorder characterized by the accumulation of two types of protein aggregates in the brain: extracellular amyloid-β plaques and intracellular tau neurofibrillary tangles. Today, it is recognized as an uncurable, age-related disease and the leading cause of dementia. The hallmark protein aggregates of Alzheimer's disease can be visualized and studied in brain tissue sections using fluorescent organic probes, which can also be radiolabeled to generate positron emission tomography (PET) tracers for diagnostic applications. PI-2620 is a tau-selective PET tracer characterized by high affinity for tau aggregates and low off-target binding. Thiophene-based analogues of PI-2620 have previously been synthesized from phenylhydrazine and thiophene-derived substrates. Herein, seven novel analogues containing a pyridine ring in place of the phenyl moiety were synthesized and evaluated. While the unsubstituted tricyclic core scaffold lacked both fluorescence and binding to protein aggregates, all substituted analogues except one functioned as fluorescent organic probes. The position of the pyridine nitrogen proved crucial for protein aggregate binding, as three isomers displayed either no staining, tau-selective staining, or Aβ-selective staining. Similar effects were observed when altering the position of the sulfur atom within the tricyclic core. Binding properties were further influenced by the nature of the terminal functionality. The terminal thienyl group of an Aβ-selective probe was replaced with a 3,4-dimethoxyphenyl group for retained selectivity, whereas the corresponding analogue bearing a terminal methyl thiophene-5-carboxylate moiety stained both Aβ and tau aggregates. In total, five novel fluorescent probes were obtained, further expanding the family of thiophene-based PI-2620 analogues.