Identification and in vitro characterization of C05-01, a PPB3 derivative with improved affinity for alpha-synuclein

Patricia Miranda-Azpiazu, Marie Svedberg, Makoto Higuchi, Maiko Ono, Zhisheng Jia, Dan Sunnemark, Charles S. Elmore, Magnus Schou, Andrea Varrone

研究成果: ジャーナルへの寄稿学術論文査読

22 被引用数 (Scopus)

抄録

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.

本文言語英語
論文番号147131
ジャーナルBrain Research
1749
DOI
出版ステータス出版済み - 15-12-2020
外部発表はい

All Science Journal Classification (ASJC) codes

  • 神経科学一般
  • 分子生物学
  • 臨床神経学
  • 発生生物学

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