Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [¹⁸F]-F0502B, which shows high binding affinity for α-Syn, but not for Aβ or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [¹⁸F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [¹⁸F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.

突触核蛋白病的特征是 α-突触核蛋白 (α-Syn) 在大脑中聚集。突触核蛋白病的正电子发射断层扫描 (PET) 成像需要选择性结合 α-Syn 沉积物的放射性药物。我们报告了一种脑可渗透且快速冲洗的 PET 示踪剂 [ ¹⁸ F]-F0502B的鉴定，该示踪剂对 α-Syn 显示出高结合亲和力，但对 Aβ 或 Tau 纤维没有，并且优先与脑切片中的 α-Syn 聚集体结合。对来自多个小鼠模型和人类受试者的体外原纤维、神经元内聚集物和神经退行性疾病脑切片进行多个周期的反筛选，[ ¹⁸ F]-F0502B 对小鼠和非人类灵长类 PD 模型大脑中的 α-Syn 沉积物进行成像。我们进一步通过冷冻电镜确定了 α-Syn 原纤维-F0502B 复合物的原子结构，并通过配体间相互作用通过强烈的非共价键合网络揭示了 F0502B 在原纤维表面上的平行对角堆积。因此，[ ¹⁸ F]-F0502B 是一种有前途的先导化合物，用于对突触核蛋白病中聚集的 α-Syn 进行成像。