MassGeneral Institute of Neurodegenerative Disease, Massachusetts General Hospital, 114 16th Street, Charlestown, MA, 02129, USA.
Mol Imaging Biol. 2013 Oct;15(5):585-95. doi: 10.1007/s11307-013-0634-y.
The goal was to identify molecular imaging probes that would enter the brain, selectively bind to Parkinson's disease (PD) pathology, and be detectable with one or more imaging modalities.
A library of organic compounds was screened for the ability to bind hallmark pathology in human Parkinson's and Alzheimer's disease tissue, alpha-synuclein oligomers and inclusions in two cell culture models, and alpha-synuclein aggregates in cortical neurons of a transgenic mouse model. Finally, compounds were tested for blood-brain barrier permeability using intravital microscopy.
Several lead compounds were identified that bound the human PD pathology, and some showed selectivity over Alzheimer's pathology. The cell culture models and transgenic mouse models that exhibit alpha-synuclein aggregation did not prove predictive for ligand binding. The compounds had favorable physicochemical properties, and several were brain permeable.
Future experiments will focus on more extensive evaluation of the lead compounds as PET ligands for clinical imaging of PD pathology.
旨在鉴定能够进入大脑、选择性结合帕金森病（PD）病理学并可通过一种或多种成像方式检测的分子成像探针。
对化合物文库进行筛选，以鉴定其与人类帕金森病和阿尔茨海默病组织、α-突触核蛋白寡聚体和两种细胞培养模型中的包含物以及转基因小鼠模型中的皮质神经元中的α-突触核蛋白聚集物结合的能力。最后，使用活体显微镜检测化合物的血脑屏障通透性。
鉴定出了几种能够结合人类 PD 病理学的先导化合物，其中一些显示出对阿尔茨海默病病理学的选择性。而那些表现出α-突触核蛋白聚集的细胞培养模型和转基因小鼠模型并未证明对配体结合具有预测性。这些化合物具有良好的物理化学性质，其中一些能够穿透血脑屏障。
未来的实验将集中于更广泛地评估这些先导化合物作为 PD 病理学的 PET 配体用于临床成像。
