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Cells
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Development of PET Radiotracers for Imaging Alpha-Synuclein
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Development of PET Radiotracers for Imaging Alpha-Synuclein

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (31 May 2025) | Viewed by 2810

Special Issue Editors

Prof. Dr. Robert H. Mach

E-Mail Website
Guest Editor
Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
Interests: positron emission tomography; neurodegeneration; alpha synuclein
Special Issues, Collections and Topics in MDPI journals
Dr. Jamie Eberling

E-Mail Website
Guest Editor
The Michael J. Fox Foundation for Parkinson's Research, New York, NY, USA
Interests: positron emission tomography; Parkinson’s disease; alpha-synuclein
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The past few years have witnessed a tremendous amount of progress in the area of PET radiotracer development for imaging alpha-synuclein aggregates in synucleinopathies. There are numerous first-in-human imaging studies being conducted with carbon-aa and fluorine-18-labeled radiotracers for alpha synuclein. We have also witnessed a number of advances in the structural biology of alpha synuclein isolated from postmortem samples of PD and MSA brain. The goal of this Special Issue of Cells is to provide a comprehensive overview of the progress in PET radiotracer development in this area, one that would serve as a central resource to the PET imaging community. We have contacted you because you have made significant progress in this area, and we believe you could make an important contribution to this Special Issue of Cells. We hope that you are able to contribute to this project.

Prof. Dr. Robert H. Mach
Dr. Jamie Eberling
Guest Editors

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Keywords

  • alpha-synuclein
  • Parkinson’s disease
  • multiple system atrophy
  • positron emission tomography

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Published Papers (3 papers)

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Research

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32 pages, 10360 KiB  
Article
Development and In Vitro Characterization of [3H]GMC-058 as Radioligand for Imaging Parkinsonian-Related Proteinopathies
by 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 and Magnus Schou
Cells 2025, 14(12), 869; https://doi.org/10.3390/cells14120869 - 9 Jun 2025
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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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Development of PET Radiotracers for Imaging Alpha-Synuclein)
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Review

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31 pages, 10891 KiB  
Review
Development of Positron Emission Tomography Radiotracers for Imaging α-Synuclein Aggregates
by Xiaodi Guo, Jie Xiang, Keqiang Ye and Zhentao Zhang
Cells 2025, 14(12), 907; https://doi.org/10.3390/cells14120907 - 16 Jun 2025
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Abstract
Neurodegenerative diseases (NDDs) that are characterized by the accumulation of alpha-synuclein (α-syn) aggregates in both neurons and the non-neuronal cells of the brain are called synucleinopathies. The most common synucleinopathies includes Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), multiple system atrophy (MSA), and [...] Read more.
Neurodegenerative diseases (NDDs) that are characterized by the accumulation of alpha-synuclein (α-syn) aggregates in both neurons and the non-neuronal cells of the brain are called synucleinopathies. The most common synucleinopathies includes Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). Significant progress has been made in the development of positron emission tomography (PET) radiotracers for synucleinopathies, yielding several α-syn tracers that have entered clinical studies. However, selective α-syn imaging still faces inherent challenges. This review provides a comprehensive overview of the progress in α-syn PET radiotracers from three angles: Alzheimer’s disease (AD)-derived scaffolds, representative compound scaffolds and analogs, and the identification of α-syn tracers through high-throughput screening (HTS). We discuss the characteristics, advantages, and limitations of the tracers for preclinical and clinical application. Finally, future directions in the development of radioligands for proteinopathies are discussed. There is no clinical available PET radiotracer for imaging α-syn aggregates, but these advances have laid a key foundation for non-invasive α-syn imaging and early diagnosis of synucleinopathies. Full article
(This article belongs to the Special Issue Development of PET Radiotracers for Imaging Alpha-Synuclein)
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Other

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9 pages, 571 KiB  
Perspective
a-synuclein PET Imaging: From Clinical Utility in Multiple System Atrophy to the Possible Diagnosis of Parkinson’s Disease
by Francesca Capotosti
Cells 2025, 14(11), 834; https://doi.org/10.3390/cells14110834 - 3 Jun 2025
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Abstract
The development of PET tracers for the detection of pathological alpha-synuclein (a-synuclein) has the potential to revolutionize the diagnosis, monitoring, and therapeutic interventions of synucleinopathies, including Parkinson’s disease. The journey toward identifying effective PET imaging agents, however, has faced significant challenges due to [...] Read more.
The development of PET tracers for the detection of pathological alpha-synuclein (a-synuclein) has the potential to revolutionize the diagnosis, monitoring, and therapeutic interventions of synucleinopathies, including Parkinson’s disease. The journey toward identifying effective PET imaging agents, however, has faced significant challenges due to the complexity and heterogeneity of the a-synuclein structures. Achieving the goal is further compounded by the low density of the pathological target, necessitating that the tracer exhibits a high binding potential, as well as the co-existence of other protein aggregates, requiring the tracer to be highly specific and selective for a-synuclein. In this perspective article, the challenges regarding developing PET tracers for a-synuclein are explored and summarized, together with the most significant recent advances in the field. These include the approaches used by our laboratories, leading to the publication of the first clinical PET images of a-synuclein pathology in patients with multiple system atrophy (MSA). Building on the current understanding of the different a-synuclein species and findings based on the success of PET tracers in the field of neurodegenerative diseases, future directions are considered also to achieve the imaging of a-synuclein pathology in Parkinson’s patients. Full article
(This article belongs to the Special Issue Development of PET Radiotracers for Imaging Alpha-Synuclein)
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