Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy

Cairns, Andrew G.; Vázquez-Romero, Ana; Moein, Mohammad Mahdi; Ådén, Jörgen; Elmore, Charles S.; Takano, Akihiro; Arakawa, Ryosuke; Varrone, Andrea; Almqvist, Fredrik; Schou, Magnus

doi:10.1021/acschemneuro.8b00236

Cited by 8 publications

(8 citation statements)

References 27 publications

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“…In 2018, Cairns et al developed a first PET tracer based on FN075 . In order to increase the brain accumulation, they exploited a prodrug approach, masking the carboxylic acid as an acetoxymethyl ester, which was designed to be unstable in vivo and release FN075 within the brain [ 143 , 146 ]. The authors reasoned that the carboxylic acid moiety disabled the compound’s ability to enter the brain as it becomes deprotonated at physiological pH.…”

Section: Alpha-synuclein Pet Tracer Development—from a Molecular Development Point Of Viewmentioning

confidence: 99%

“…[ 11 C]85 was able to cross the BBB, showing a slow washed out whereas [ 11 C]84 did not enter the brain ( Figure 28 B). The authors speculated that [ 11 C]85 was hydrolyzed within the brain however this needs to be proved conclusively [ 146 ]. Further studies are needed to determine the potential of FN075 analogues as possible agents for the imaging of α-syn fibrillization.…”

Section: Alpha-synuclein Pet Tracer Development—from a Molecular Development Point Of Viewmentioning

confidence: 99%

“…( A ) The chemical structures of FN075 and radiolabeled acetoxymethyl ester [ 11 C]84 and [ 11 C]85 . ( B ) TACs in the whole brain derived from healthy NHP following the IV injection of [ 11 C]84 and [ 11 C]85 (reprinted with permission from [ 146 ]. Copyright 2018 American Chemical Society).…”

Section: Figurementioning

confidence: 99%

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

et al. 2021

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Neurodegenerative diseases such as Parkinson’s disease (PD) are manifested by inclusion bodies of alpha-synuclein (α-syn) also called α-synucleinopathies. Detection of these inclusions is thus far only possible by histological examination of postmortem brain tissue. The possibility of non-invasively detecting α-syn will therefore provide valuable insights into the disease progression of α-synucleinopathies. In particular, α-syn imaging can quantify changes in monomeric, oligomeric, and fibrillic α-syn over time and improve early diagnosis of various α-synucleinopathies or monitor treatment progress. Positron emission tomography (PET) is a non-invasive in vivo imaging technique that can quantify target expression and drug occupancies when a suitable tracer exists. As such, novel α-syn PET tracers are highly sought after. The development of an α-syn PET tracer faces several challenges. For example, the low abundance of α-syn within the brain necessitates the development of a high-affinity ligand. Moreover, α-syn depositions are, in contrast to amyloid proteins, predominantly localized intracellularly, limiting their accessibility. Furthermore, another challenge is the ligand selectivity over structurally similar amyloids such as amyloid-beta or tau, which are often co-localized with α-syn pathology. The lack of a defined crystal structure of α-syn has also hindered rational drug and tracer design efforts. Our objective for this review is to provide a comprehensive overview of current efforts in the development of selective α-syn PET tracers.

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Section: Alpha-synuclein Pet Tracer Development—from a Molecular Development Point Of Viewmentioning

confidence: 99%

Section: Alpha-synuclein Pet Tracer Development—from a Molecular Development Point Of Viewmentioning

confidence: 99%

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

et al. 2021

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“…We will also need to develop PET‐tracers that can detect aSyn, to enable longitudinal studies in patients, and even in individuals at risk (based on genetic factors, for example). Attempts to develop radioligands able to bind to different forms of aSyn are ongoing, but we still face major challenges such as selectivity, or blood–brain barrier penetration (Cairns et al, ; Merchant et al, ; Verdurand et al, ). However, the coming years may bring novel developments in this area.…”

Section: Pd Biomarkers Based On Asynmentioning

confidence: 99%

Synucleinopathies: Where we are and where we need to go

Brás

Dominguez-Meijide

Gerhardt

et al. 2020

Journal of Neurochemistry

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All authors contributed equally to this manuscript. This artic le is relat ed to the Speci al Issue "Synuc lein" Abbreviations: A30P, aSyn substitution of an alanine for a proline at position 30; A53E, aSyn substitution of an alanine for a glutamic acid at position 53; A53T, aSyn substitution of an alanine for a tyrosine at position 53; ALP, autophagy-lysosomal pathway; APLP1, Aβ precursor-like protein 1; aSyn, alpha-synuclein; BiFC, bimolecular fluorescence complementation; CMA, Chaperone-mediated autophagy; CNS, central nervous system; co-IP, co-immunoprecipitation; Cryo-EM, cryo-electron microscopy; CSF, cerebrospinal fluid; Cu, copper; DLB, dementia with Lewy bodies; E46K, aSyn substitution of a glutamic acid for a lysine at position 46; ENS, enteric nervous system; ER, endoplasmic reticulum; Fe, iron; FRET, fluorescence resonance energy transfer; G51D, aSyn substitution of a glycine for a aspartic acid at position 51Abstract Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019:Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.

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“…coli., [1][2] Listeria and Chlamydia infections [3][4][5] and modulators of protein aggregation associated with neurodegenerative diseases. [6][7][8][9][10][11][12][13] In a recent study, a cyclopropyl analogue (Figure 1, A) was shown to inhibit Mycobacterium tuberculosis (Mtb) ability to convert into its tolerant state. These compounds were named Mycobacterial Tolerance Inhibitors (MTIs) and besides sensitizing Mtb to host defense responses (e.g.…”

Section: Introductionmentioning

confidence: 99%

An efficient and scalable synthesis of thiazolo ring fused 2-pyridones using flow chemistry

Cairns¹,

Sarkar²,

Singh³

et al. 2021

Arkivoc

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Thiazolino ring fused 2-pyridones are a valuable scaffold with varied and substitution dependent biological activity, accessed primarily by an acyl ketene-imine cycloaddition and rearrangement. Although powerful, some aspects of this chemistry such as the requirement for excess starting material and the production of gas can make larger scale synthesis challenging. Here we describe the development, application and scaling of a continuous flow process allowing larger scale synthesis, with better handling of hazards and more reliable scaling. Optimisation and control of conditions allows for a more efficient synthesis, with a lower equivalence of the acyl ketene precursor required.

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Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy

Cited by 8 publications

References 27 publications

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

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

Synucleinopathies: Where we are and where we need to go

An efficient and scalable synthesis of thiazolo ring fused 2-pyridones using flow chemistry

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