Alpha-Synuclein PET Tracer Development—An Overview about Current Efforts

Dementia with Lewy Bodies (DLB) is a common form of cognitive neurodegenerative disease. Only one third of patients are correctly diagnosed due to the clinical similarity mainly with Alzheimer’s disease (AD). In this review, we evaluate the interest of different biomarkers: cerebrospinal fluid (CSF), brain MRI, FP-CIT SPECT, MIBG SPECT, PET by focusing more specifically on differential diagnosis between DLB and AD. FP-CIT SPECT is of high interest to discriminate DLB and AD, but not at the prodromal stage (i.e., MCI). MIBG SPECT with decreased cardiac sympathetic activity, perfusion SPECT with occipital hypoperfusion, FDG PET with occipital hypometabolism and cingulate island signs are of interest at the dementia stage but with a lower validity. Brain MRI has shown differences in group study with lower grey matter concentration of the Insula in prodromal DLB, but its interest in clinical routines is not demonstrated. Concerning CSF biomarkers, many studies have already examined the relevance of AD biomarkers but also alpha-synuclein assays in DLB, so we will focus as comprehensively as possible on other biomarkers (especially those that do not appear to be directly related to synucleinopathy) that may be of interest in the differential diagnosis between AD and DLB. Furthermore, we would like to highlight the growing interest in CSF synuclein RT-QuIC, which seems to be an excellent discrimination tool but its application in clinical routine remains to be demonstrated, given the non-automation of the process.

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“…There are many efforts to obtain a specific biomarker for synucleopathies in PET [ 50 ]. Alpha-synuclein PET is still missing.…”

Section: Brain Imaging Diagnostic Biomarkersmentioning

confidence: 99%

Biomarkers of Dementia with Lewy Bodies: Differential Diagnostic with Alzheimer’s Disease

Bousiges

Blanc

2022

IJMS

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“…Imaging of α -syn toxic aggregates (oligomeric, fibrillic) could be a useful tool not only for early diagnosis of disease but also for its development. Recently Xu et al [ 52 ] and Korat et al [ 53 ] reviewed the progression of this strategy. Development of radiotracers for positron emission tomography (PET) targeting α -synucleinopathies is very challenging.…”

Section: Targeting α -Synucleinmentioning

confidence: 99%

“…Development of radiotracers for positron emission tomography (PET) targeting α -synucleinopathies is very challenging. There are certain requirements that should be met [ 53 ]: Very high affinity for α -syn (even in the subnanomolar range); High selectivity of imaging α -syn (quantify α -syn in the presence of higher density of Aβ or/and tau proteins); Good permeability to cross not only BBB but cell membranes; Low binding to off-targets (>500 nM); Good metabolic stability. …”

Section: Targeting α -Synucleinmentioning

confidence: 99%

Chalcones as Potential Ligands for the Treatment of Parkinson’s Disease

2022

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Along with the increase in life expectancy, a significant increase of people suffering from neurodegenerative diseases (ND) has been noticed. The second most common ND, after Alzheimer’s disease, is Parkinson’s disease (PD), which manifests itself with a number of motor and non-motor symptoms that hinder the patient’s life. Current therapies can only alleviate those symptoms and slow down the progression of the disease, but not effectively cure it. So now, in addition to understanding the mechanism and causes of PD, it is also important to find a powerful way of treatment. It has been proved that in the etiology and course of PD, the essential roles are played by dopamine (DA) (an important neurotransmitter), enzymes regulating its level (e.g., COMT, MAO), and oxidative stress leading to neuroinflammation. Chalcones, due to their “simple” structure and valuable biological properties are considered as promising candidates for treatment of ND, also including PD. Here, we provide a comprehensive review of chalcones and related structures as potential new therapeutics for cure and prevention of PD. For this purpose, three databases (Pubmed, Scopus and Web of Science) were searched to collect articles published during the last 5 years (January 2018–February 2022). Chalcones have been described as promising enzyme inhibitors (MAO B, COMT, AChE), α-synuclein imaging probes, showing anti-neuroinflammatory activity (inhibition of iNOS or activation of Nrf2 signaling), as well as antagonists of adenosine A1 and/or A2A receptors. This review focused on the structure–activity relationships of these compounds to determine how a particular substituent or its position in the chalcone ring(s) (ring A and/or B) affects biological activity.

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“…In a group of neurodegenerative disorders (NDDs) known as the α-synucleinopathies, the highly soluble presynaptic protein α-synuclein (Uéda et al, 1993;Spillantini et al, 1998;Clayton and George, 1999;Vilar et al, 2008;Uzuegbunam et al, 2020;Korat et al, 2021) is predominantly present as fibrillary insoluble protein aggregates (α-syn) included in Lewy bodies (LB), Lewy neurites (LN), and glial cytoplasmic inclusions (GCI). NDDs characterized by α-syn deposition include Parkinson's disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA) (Tu et al, 1998;Wakabayashi et al, 1998;Spillantini and Goedert, 2000;Burré et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Increasing progress has been made so far in the development of selective PET radioligands for the imaging of the biomarkers of other NDDs like Alzheimer's disease and tauopathies, some of which have gained also regulatory approval such as the tau tracer Flortaucipir (Neurology live, 2021) and the β-amyloid tracers Neuraceq (FDA/CDERB) 1 , Amyvid (FDA/CDERA) 2 , and Vizamyl (FDA) 3 while some have made to it clinical studies. For the α-synucleinopathies, there is yet to be a radiotracer, which has made it past the preclinical stages (Verdurand et al, 2018;Uzuegbunam et al, 2020;Korat et al, 2021). This could be owing to the following reasons: low binding affinity to α-syn, suboptimal selectivity for α-syn in comparison to Aβ and tau (Ono et al, 2016) with a similar β-sheet core structure (Miranda-Azpiazu et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Toward Novel [18F]Fluorine-Labeled Radiotracers for the Imaging of α-Synuclein Fibrils

Uzuegbunam

Paslawski

et al. 2022

Front. Aging Neurosci.

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The accumulation of α-synuclein aggregates (α-syn) in the human brain is an occurrence common to all α-synucleinopathies. Non-invasive detection of these aggregates in a living brain with a target-specific radiotracer is not yet possible. We have recently discovered that the inclusion of a methylenedioxy group in the structure of diarylbisthiazole (DABTA)-based tracers improves binding affinity and selectivity to α-syn. Subsequently, complementary in silico modeling and machine learning (ML) of tracer–protein interactions were employed to predict surface sites and structure–property relations for the binding of the ligands. Based on this observation, we developed a small focused library of DABTAs from which 4-(benzo[d][1,3]dioxol-5-yl)-4′-(3-[18F]fluoro-4-methoxyphenyl)-2,2′-bithiazole [18F]d2, 6-(4′-(3-[18F]fluoro-4-methoxyphenyl)-[2,2′-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [18F]d4, 4-(benzo [d][1,3]dioxol-5-yl)-4′-(6-[18F]fluoropyridin-3-yl)-2,2′-bithiazole [18F]d6, and 6-(4′-(6-[18F]fluoropyridin-3-yl)-[2,2′-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [18F]d8 were selected based on their high binding affinity to α-syn and were further evaluated. Binding assay experiments carried out with the non-radioactive versions of the above tracers d2, d4, d6, and d8 showed high binding affinity of the ligands to α-syn: 1.22, 0.66, 1.21, and 0.10 nM, respectively, as well as excellent selectivity over β-amyloid plaques (Aβ) and microtubular tau aggregates (>200-fold selectivity). To obtain the tracers, their precursors were radiolabeled either via an innovative ruthenium-mediated (SNAr) reaction ([18F]d2 and [18F]d4) or typical SNAr reaction ([18F]d6 and [18F]d8) with moderate-to-high radiochemical yields (13% – 40%), and high molar activity > 60 GBq/μmol. Biodistribution experiments carried out with the tracers in healthy mice revealed that [18F]d2 and [18F]d4 showed suboptimal brain pharmacokinetics: 1.58 and 4.63 %ID/g at 5 min post-injection (p.i.), and 1.93 and 3.86 %ID/g at 60 min p.i., respectively. However, [18F]d6 and [18F]d8 showed improved brain pharmacokinetics: 5.79 and 5.13 %ID/g at 5 min p.i.; 1.75 and 1.07 %ID/g at 60 min p.i.; and 1.04 and 0.58 %ID/g at 120 min p.i., respectively. The brain uptake kinetics of [18F]d6 and [18F]d8 were confirmed in a dynamic PET study. Both tracers also showed no brain radiometabolites at 20 min p.i. in initial in vivo stability experiments carried out in healthy mice. [18F]d8 seems very promising based on its binding properties and in vivo stability, thus encouraging further validation of its usefulness as a radiotracer for the in vivo visualization of α-syn in preclinical and clinical settings. Additionally, in silico and ML-predicted values correlated with the experimental binding affinity of the ligands.

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Alpha-Synuclein PET Tracer Development—An Overview about Current Efforts

Cited by 60 publications

References 145 publications

Biomarkers of Dementia with Lewy Bodies: Differential Diagnostic with Alzheimer’s Disease

Biomarkers of Dementia with Lewy Bodies: Differential Diagnostic with Alzheimer’s Disease

Chalcones as Potential Ligands for the Treatment of Parkinson’s Disease

Toward Novel [18F]Fluorine-Labeled Radiotracers for the Imaging of α-Synuclein Fibrils

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