Publication date: Jun 09, 2025
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: Ki < 30 nM, Ki and Ki > 200 nM. Three compounds, GMC-073 (K: 8 nM), GMC-098 (Ki: 9. 7 nM), and GMC-058 (Ki: 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 K was highest in AD (5. 4 nM), followed by PSP (41 nM) and CBD (75 nM). The K 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.
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Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | Proteinopathies |
| disease | MESH | Parkinson’s disease |
| disease | MESH | movement disorders |
| disease | MESH | Alzheimer’s disease |
| disease | MESH | atrophy |
| disease | MESH | cerebral amyloid angiopathy |
| disease | MESH | progressive supranuclear palsy |
| disease | MESH | corticobasal degeneration |
| drug | DRUGBANK | Cannabidiol |
| disease | MESH | tauopathies |
| pathway | KEGG | Alzheimer disease |
| pathway | KEGG | Parkinson disease |