Development and In Vitro Characterization of [<sup>3</sup>H]GMC-058 as Radioligand for Imaging Parkinsonian-Related Proteinopathies
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 s...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
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| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/12/869 |
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| Summary: | 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>K</i>i<sub>α-syn</sub> < 30 nM, <i>K</i>i<sub>tau</sub> and <i>K</i>i<sub>A-β</sub> > 200 nM. Three compounds, GMC-073 (<i>K</i><sub>iα-syn</sub>: 8 nM), GMC-098 (<i>K</i>i<sub>α-syn</sub>: 9.7 nM), and GMC-058 (<i>K</i>i<sub>α-syn</sub>: 22.5 nM), fulfilled the criteria and were radiolabeled with <sup>3</sup>H. [<sup>3</sup>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. [<sup>3</sup>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 <i>K</i><sub>D</sub> was highest in AD (5.4 nM), followed by PSP (41 nM) and CBD (75 nM). The <i>K</i><sub>D</sub> in MSA, PD, and controls was >100 nM. [<sup>3</sup>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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| ISSN: | 2073-4409 |