O'Shea Jennifer Y, Dhavale Dhruva D, Hwang Helen, Smith Zachary, Graham Thomas J A, Mach Robert H, Kotzbauer Paul T
Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cells. 2025 Sep 22;14(18):1477. doi: 10.3390/cells14181477.
Parkinson's disease (PD) and Lewy Body Dementia (LBD) are defined by accumulation of alpha-synuclein (Asyn) fibrils within Lewy bodies (LBs) and Lewy neurites (LNs). The development of a Positron Emission Tomography (PET) tracer for quantifying Asyn fibrils would improve diagnostic accuracy and provide a biomarker for disease progression. We previously described radioligand [H]Tg-1-90B, which binds to in vitro Asyn fibrils (PDB 2N0A) via interactions with residues Y39, S42 and K44. Here, we performed molecular docking studies with Tg1-90B and PD/LBD Asyn fibrils (PDB 8A9L), which predicts interactions with residues Y39 and K43 in a structurally distinct binding site. In radioligand binding assays, Tg-1-90B has moderate to high affinity (K 17.5 nM) for amplified LBD fibrils (PDB 8FPT), whose protofilament fold is highly similar to PD/LBD fibrils (PBD 8A9L). Autoradiography confirmed binding of [H]Tg-1-90B to LBs in PD brain tissue. However, Tg-1-90B also binds to amyloid-beta fibrils in Alzheimer's disease (AD) tissue, indicating insufficient selectivity for Asyn fibrils. These results indicate that Tg-1-90B binds to Asyn fibrils in PD tissue but needs further structural optimization. Binding assays with amplified LBD fibrils and autoradiography with postmortem PD tissue can guide further development of Asyn fibril PET ligands for PD/LBD.
帕金森病（PD）和路易体痴呆（LBD）是由路易小体（LBs）和路易神经突（LNs）内α-突触核蛋白（Asyn）纤维的积累所定义的。开发一种用于定量Asyn纤维的正电子发射断层扫描（PET）示踪剂将提高诊断准确性，并为疾病进展提供生物标志物。我们之前描述了放射性配体[H]Tg-1-90B，它通过与Y39、S42和K44残基的相互作用与体外Asyn纤维（PDB 2N0A）结合。在这里，我们用Tg1-90B和PD/LBD Asyn纤维（PDB 8A9L）进行了分子对接研究，该研究预测了在结构上不同的结合位点与Y39和K43残基的相互作用。在放射性配体结合试验中，Tg-1-90B对扩增的LBD纤维（PDB 8FPT）具有中度至高亲和力（K 17.5 nM），其原纤维折叠与PD/LBD纤维（PBD 8A9L）高度相似。放射自显影证实了[H]Tg-1-90B与PD脑组织中LBs的结合。然而，Tg-1-90B也与阿尔茨海默病（AD）组织中的淀粉样β纤维结合，表明对Asyn纤维的选择性不足。这些结果表明，Tg-1-90B与PD组织中的Asyn纤维结合，但需要进一步的结构优化。用扩增的LBD纤维进行结合试验和用死后PD组织进行放射自显影可以指导用于PD/LBD的Asyn纤维PET配体的进一步开发。
