Development and In Vitro Characterization of [3H]GMC-058 as Radioligand for Imaging Parkinsonian-Related Proteinopathies
Andrea Varrone, Vasco C. Sousa, Manolo Mugnaini, Sandra Biesinger, Gunnar Nordvall, Lee Kingston, Ileana Guzzetti, Charles S. Elmore, Dan Sunnemark, Dinahlee Saturnino Guarino, Sjoerd J. Finnema, Magnus Schou
TL;DR
Researchers developed and tested a new radioligand, [3H]GMC-058, that can detect abnormal protein deposits linked to Parkinson's disease and related disorders in laboratory experiments.
Contribution
The study introduces [3H]GMC-058 as a novel radioligand with potential for imaging α-synuclein and tau pathologies in neurodegenerative diseases.
Findings
[3H]GMC-058 showed specific binding to α-synuclein inclusions in Parkinson’s disease and multiple-system atrophy.
The radioligand also co-localized with tau pathology in progressive supranuclear palsy and corticobasal degeneration.
In vitro KD values indicated highest binding affinity in Alzheimer’s disease followed by tauopathies.
Abstract
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…
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Taxonomy
TopicsNeurological disorders and treatments · Parkinson's Disease Mechanisms and Treatments · Nuclear Receptors and Signaling