Patricia Miranda-Azpiazua, Marie Svedberga, Makoto Higuchib, Maiko Onob, Zhisheng Jiaa,Dan Sunnemarkc, Charles S. Elmoree, Magnus Schoua, Andrea Varronea
Brain Research, 2020 Sep 14; 1749 (2020) 147131
DOI: https://doi.org/10.1016/j.brainres.2020.147131
Abstract
The neuropathological hallmark of Parkinsońs disease, multiple system atrophy and dementia with Lewy bodies is the accumulation of α-synuclein. The development of an imaging biomarker for α-synuclein is an unmet need. To date, no selective α-synuclein imaging agent has been identified, though initial studies suggest that the tau tracer [11C]PBB3 displays some degree of binding to α-synuclein. In this study, a series of compounds derived from the PBB3 scaffold were examined using fluorescence imaging and tissue microarrays (TMAs) derived from brain samples with different proteinopathies. One compound, C05-01, was selected based on its higher fluorescence signal associated with Lewy body aggregates compared with other PBB3 analogues. In vitro binding assays using human brain homogenates and recombinant fibrils indicated that C05-01 had higher affinity for α-synuclein (KD/Ki 25 nM for fibrils, Ki 3.5 nM for brain homogenates) as compared with PBB3 (KD 58 nM). In autoradiography (ARG) studies using fresh frozen human tissue and TMAs, [3H]C05-01 displayed specific binding in cases with α-synuclein pathology. C05-01 is the first PBB3 analogue developed as a potential compound targeting α-synuclein. Despite improved affinity for α-synuclein, C05-01 showed specific binding in AD tissue with Amyloid β and tau pathology, as well as relatively high non-specific and off-target binding. Additional efforts are needed to optimize the pharmacological and physicochemical properties of this series of compounds as ligands for α-synuclein. This study also showed that the construction of TMAs from different proteinopathies provides a tool for evaluation of fluorescent or radiolabelled compounds binding to misfolded proteins.
The identification and in vitro characterization of C05-01 are truly remarkable achievements, shedding light on its potential applications in various fields. The thorough exploration of its properties opens doors to innovative research avenues and possible therapeutic interventions. Moreover, leveraging upwork SEO services can amplify the dissemination of this groundbreaking discovery, ensuring it reaches a broader audience and catalyzes further scientific inquiry. This meticulous study not only expands our understanding of C05-01 but also paves the way for its practical utilization, ultimately contributing to advancements in biomedicine and beyond.