Development of an α-synuclein (α-Syn) positron emission tomography agent for the diagnosis and evaluation of Parkinson disease therapy is a key goal of neurodegenerative disease research. BF-227 has been described as an α-Syn binder and hence was employed as a lead to generate a library of α-Syn-binding compounds. [3H]BF-227 bound to α-Syn and amyloid β peptide (Aβ) fibrils with affinities (KD) of 46.0 nM and 15.7 nM, respectively. Affinities of BF-227-like compounds (expressed as Ki) for α-Syn and Aβ fibrils were determined, along with 5 reference compounds (flutafuranol, flutemetamol, florbetapir, BF-227, and PiB). Selectivity for α-Syn binding, defined as the Ki(Aβ)/Ki(α-Syn) ratio, was 0.23 for BF-227. A similar or lower ratio was measured for analogues decorated with alkyl or oxyethylene chains attached to the oxygen at the 6 position of BF-227, suggesting a lack of involvement of the side chain in fibril binding. BF-227-like iodobenzoxazoles had lower affinities and poor α-Syn selectivity. However, BF-227-like fluorobenzoxazoles had improved α-Syn selectively having Ki(Aβ)/Ki(α-Syn) ranging from 2.2 to 5.1 with appreciable fibril affinity, although not sufficient to warrant further investigation. Compounds based on fluorobenzoxazoles might offer an approach to obtaining an α-Syn imaging agent with an appropriate affinity and selectivity.

中文翻译：

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类似于BF-227的苯并恶唑与人α-突触核蛋白和淀粉样β肽原纤维的结合。

开发用于诊断和评估帕金森病疗法的α-突触核蛋白（α-Syn）正电子发射断层显像剂是神经退行性疾病研究的关键目标。BF-227被描述为一种α-Syn粘合剂，因此被用作生成α-Syn结合化合物库的先导。[3H] BF-227分别以46.0 nM和15.7 nM的亲和力（KD）结合到α-Syn和淀粉样β肽（Aβ）原纤维上。确定了BF-227类化合物（以Ki表示）对α-Syn和Aβ原纤维的亲和力，以及5种参比化合物（氟氢呋喃醇，氟美他莫，florbetapir，BF-227和PiB）的亲和力。对于BF-227，α-Syn结合的选择性定义为Ki（Aβ）/ Ki（α-Syn）比，为0.23。对于用BF-227的6位上的氧连接的烷基或氧乙烯链修饰的类似物，测得的相似或更低的比率，表明侧链缺乏参与原纤维的结合。BF-227样碘代苯并恶唑具有较低的亲和力和较差的α-Syn选择性。然而，BF-227样氟苯并恶唑具有明显的原纤维亲和力，选择性改善了Ki（Aβ）/ Ki（α-Syn）范围从2.2至5.1的α-Syn，尽管不足以保证进一步的研究。基于氟苯并恶唑的化合物可能提供一种以适当的亲和力和选择性获得α-Syn成像剂的方法。BF-227-like氟代苯并恶唑具有明显的原纤维亲和力，选择性改善了Ki-（Aβ）/ Ki（α-Syn）范围从2.2至5.1的α-Syn，尽管不足以保证进一步的研究。基于氟苯并恶唑的化合物可能提供一种以适当的亲和力和选择性获得α-Syn成像剂的方法。BF-227-like氟代苯并恶唑具有明显的原纤维亲和力，选择性改善了Ki-（Aβ）/ Ki（α-Syn）范围从2.2至5.1的α-Syn，尽管不足以保证进一步的研究。基于氟苯并恶唑的化合物可能提供一种以适当的亲和力和选择性获得α-Syn成像剂的方法。