Varrone Andrea, Sousa Vasco C, Mugnaini Manolo, Biesinger Sandra, Nordvall Gunnar, Kingston Lee, Guzzetti Ileana, Elmore Charles S, Sunnemark Dan, Saturnino Guarino Dinahlee, Finnema Sjoerd J, Schou Magnus
Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm Health Services, BioClinicum, J4-14, Akademiska Stråket 1, 17176 Solna, Sweden.
Department of Clinical Neuroscience, Division of Imaging Core Facilities, Karolinska Institutet, Stockholm, Sweden, BioClinicum, J5, Akademiska Stråket 1, 17176 Solna, Sweden.
Cells. 2025 Jun 9;14(12):869. doi: 10.3390/cells14120869.
The molecular imaging of α-synuclein (α-syn) pathology in Parkinson's disease (PD) and related movement disorders is a clinically unmet need. The aim of this study was to discover and characterize in vitro a radioligand for imaging α-syn pathology. A library of 78 small molecules was developed and screened using recombinant α-syn fibrils and brain homogenates from Alzheimer's disease (AD) donors. The selection criteria were as follows: i < 30 nM, i and i > 200 nM. Three compounds, GMC-073 (: 8 nM), GMC-098 (i: 9.7 nM), and GMC-058 (i: 22.5 nM), fulfilled the criteria and were radiolabeled with H. [H]GMC-058 was the only compound with negligible binding in controls, and was further evaluated using tissue microarrays, autoradiography on fresh-frozen brain slices, and in vitro saturation binding assay on brain homogenates. [H]GMC-058 binding co-localized with α-syn inclusions in Parkinson's disease (PD) and multiple-system atrophy (MSA), with dense A-β plaques in cerebral amyloid angiopathy and AD and with p-tau inclusions in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Specific binding was highest in PSP and CBD. In vitro was highest in AD (5.4 nM), followed by PSP (41 nM) and CBD (75 nM). The in MSA, PD, and controls was >100 nM. [H]GMC-058 is a novel radioligand displaying a low affinity for aggregated α-syn in tissue, with an in vitro profile also suitable for detecting tau pathology in 4R tauopathies.
帕金森病（PD）及相关运动障碍中α-突触核蛋白（α-syn）病理的分子成像在临床上是尚未满足的需求。本研究的目的是在体外发现并表征一种用于成像α-syn病理的放射性配体。开发了一个包含78种小分子的文库，并使用重组α-syn原纤维和来自阿尔茨海默病（AD）供体的脑匀浆进行筛选。选择标准如下：i<30 nM，i且i>200 nM。三种化合物，GMC-073（i：8 nM）、GMC-098（i：9.7 nM）和GMC-058（i：22.5 nM）符合标准，并用H进行放射性标记。[H]GMC-058是唯一在对照中结合可忽略不计的化合物，并使用组织微阵列、新鲜冷冻脑切片的放射自显影以及脑匀浆的体外饱和结合试验进行了进一步评估。[H]GMC-058结合在帕金森病（PD）和多系统萎缩（MSA）中与α-syn包涵体共定位，在脑淀粉样血管病和AD中与致密的A-β斑块共定位，在进行性核上性麻痹（PSP）和皮质基底节变性（CBD）中与p-tau包涵体共定位。特异性结合在PSP和CBD中最高。体外KD在AD中最高（5.4 nM），其次是PSP（41 nM）和CBD（75 nM）。MSA、PD和对照中的KD>100 nM。[H]GMC-058是一种新型放射性配体，对组织中聚集的α-syn显示出低亲和力，其体外特征也适用于检测4R tau蛋白病中的tau病理。
