Development and In Vitro Characterization of [3H]GMC-058 as Radioligand for Imaging Parkinsonian-Related Proteinopathies

• Published in: Cells (Basel, Switzerland) Vol. 14; no. 12; p. 869
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.06.2025; MDPI
• Subjects: Aged; alpha-Synuclein - metabolism; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid; Atrophy; Autopsies; Autoradiography; Basal ganglia; Brain - diagnostic imaging; Brain - metabolism; Brain - pathology; Brain research; Brain slice preparation; Central nervous system diseases; Cerebral amyloid angiopathy; Dementia; Experiments; Female; Fibrils; Humans; in vitro assay; Lewy bodies; Ligands; Male; Movement disorders; Neurodegeneration; Neurodegenerative diseases; Neuroimaging; Parkinson Disease - diagnostic imaging; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathology; Progressive supranuclear palsy; proteinopathy; Radiopharmaceuticals; Sensors; Software; Synuclein; Tau protein; Tissues; United States > US; Netherlands; Germany; neurodegeneration; proteinopathy; in vitro assay; Lewy bodies
• ISSN: 2073-4409; 2073-4409
• 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: Kiα-syn < 30 nM, Kitau and KiA-β > 200 nM. Three compounds, GMC-073 (Kiα-syn: 8 nM), GMC-098 (Kiα-syn: 9.7 nM), and GMC-058 (Kiα-syn: 22.5 nM), fulfilled the criteria and were radiolabeled with 3H. [3H]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. [3H]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 KD was highest in AD (5.4 nM), followed by PSP (41 nM) and CBD (75 nM). The KD in MSA, PD, and controls was >100 nM. [3H]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.