Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies

Xiang, Jie; Tao, Youqi; Xia, Yiyuan; Luo, Shilin; Zhao, Qinyue; Li, Bowei; Zhang, Xiaoqian; Sun, Yunpeng; Xia, Wencheng; Zhang, Mingming; Kang, Seong Su; Ahn, Eun-Hee; Liu, Xia; Xie, Fang; Guan, Yihui; Yang, Jenny J.; Bu, Lihong; Wu, Shengxi; Wang, Xiaochuan; Cao, Xuebing; Liu, Cong; Zhang, Zhentao; Li, Dan; Ye, Keqiang

doi:10.1016/j.cell.2023.06.004

Cited by 30 publications

(12 citation statements)

References 72 publications

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“…In Alzheimer's disease (AD), the development of PET tracers targeting amyloid-β (Aβ) and tau aggregates has greatly advanced our understanding of the time course of aggregation and the regional spread of pathology, revolutionizing the early diagnosis of AD and the assessment of therapeutic effects. Several small molecules targeting αSYN aggregates have been developed over the past decade, with two of them being studied in human subjects [4][5][6][7]. Nonetheless, none of these molecules has been translated into clinical applications so far.…”

Section: Synucleinopathies Are Neurodegenerative Diseases Characteriz...mentioning

confidence: 99%

[11C]MODAG 005 – a novel PET tracer targeting alpha-synuclein aggregates in the brain

Saw,

Buss,

Schmidt

et al. 2024

Preprint

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Synucleinopathies are neurodegenerative diseases characterized by the presence of brain inclusions containing the pathologically aggregated protein α-synuclein (αSYN). The development of a positron emission tomography tracer to detect aggregates of misfolded αSYN would revolutionize disease monitoring and the evaluation of therapeutic efficacy. Here we present the development and preclinical in vitro and in vivo validation of [11C]MODAG-005. In vitro binding experiments demonstrate subnanomolar binding affinity to recombinant αSYN fibrils as well as to αSYN inclusions in human brain tissue. Specific binding in multiple system atrophy brain tissue was detected using autoradiography and microautoradiography, and was validated through immunostaining. In vivo, [11C]MODAG-005 shows good brain penetration, rapid clearance from brain tissue and low metabolite formation in rodents and non-human primates. In addition, a pronounced binding and a good signal-to-noise ratio were achieved in an αSYN fibril-injected rat model and in an αSYN(A30P) transgenic mouse model in correlation to the pathological load. To validate its value for therapy development, we show target engagement of the drug candidate anle138b in the brain tissues from αSYN(A30P) mouse and multiple system atrophy as well as in vivo in αSYN fibril-injected rats. Finally, our translational approach in a first-in-human patient with clinically established MSA, revealed a marked tracer binding in regions affected by αSYN pathology, particularly in the striatum, where the pattern corresponded with the neurodegeneration shown by dopamine transporter single-photon emission computed tomography.

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Section: Synucleinopathies Are Neurodegenerative Diseases Characteriz...mentioning

confidence: 99%

[11C]MODAG 005 – a novel PET tracer targeting alpha-synuclein aggregates in the brain

Saw,

Buss,

Schmidt

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…This compound showed promising results in successfully binding with α-synuclein fibrils in both live and fixed brain tissues of rodent and non-human primate PD models. 19 However, it has not yet been used in human subjects. PET tracers for identifying other types of synucleinopathies are also being carried out by different researchers, which brings new hope for early disease diagnosis and tracing disease progression.…”

Section: Molecular Imagingmentioning

confidence: 99%

A review on the new age methodologies for early detection of Alzheimer's and Parkinson's disease

Ghosh,

Sinha,

Sil

2024

Basic Clin Pharma Tox

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BackgroundsNeurodegenerative diseases (NDDs) such as Alzheimer's (AD) and Parkinson's (PD) are often diagnosed late, impeding effective treatment; therefore, early detection is imperative. Modern methodologies can serve a pivotal role in fulfilling the crucial need for timely detection and intervention in this context.ObjectivesEvaluate early detection's significance and summarize key technologies (biomarkers, neuroimaging, AI/ML, genetics, digital health) for enhanced diagnostic strategies in AD and PD.MethodsThis study employs a focused descriptive review approach, encompassing analysis of peer‐reviewed articles and clinical trials from existing literature, to provide a nuanced exploration of the subject matter.FindingsThis review underscores the efficacy of non‐invasive biomarkers, biosensors and emerging promising technologies for advancing early diagnosis of AD and PD.ConclusionThe landscape of early NDD detection has been reshaped by technology, yet challenges persist, encompassing the domains of validation and ethics. A collaborative effort between medical professionals, researchers and technologists is imperative to effectively address and combat NDDs.

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“…Common neurodegenerative diseases include Parkinson’s, Huntington’s, Alzheimer’s disease, amyotrophic lateral sclerosis, and prion disease, among others. With the ageing population, Parkinson’s and Alzheimer’s diseases stand as the top two neurodegenerative diseases, posing significant threats to the life and health of the elderly(Xiang et al 2023 ). Huntington’s disease, a typical autosomal dominant neurodegenerative disease, results from a gene mutation.…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Yuan,

She,

Jiang

et al. 2024

Mol Med

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The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads to endoplasmic reticulum stress (ER stress). As ER stress ensues, the unfolded protein response (UPR), comprising three signaling pathways—inositol-requiring enzyme 1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor 6 promptly activates to enhance the ER’s protein-folding capacity and restore ER homeostasis. However, prolonged ER stress levels propels the UPR towards cellular demise and the subsequent inflammatory cascade, contributing to the development of human diseases, including cancer, neurodegenerative disorders, and diabetes. Notably, increased expression of all three UPR signaling pathways has been observed in these pathologies, and reduction in signaling molecule expression correlates with decreased proliferation of disease-associated target cells. Consequently, therapeutic strategies targeting ER stress-related interventions have attracted significant research interest. In this review, we elucidate the critical role of ER stress in cancer, metabolic, and neurodegenerative diseases, offering novel therapeutic approaches for these conditions.

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Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies

Cited by 30 publications

References 72 publications

[11C]MODAG 005 – a novel PET tracer targeting alpha-synuclein aggregates in the brain

[11C]MODAG 005 – a novel PET tracer targeting alpha-synuclein aggregates in the brain

A review on the new age methodologies for early detection of Alzheimer's and Parkinson's disease

Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

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