An HPLC-UV validated bioanalytical method for measurement of <i>in vitro</i> phase 1 kinetics of α-synuclein binding bifunctional compounds

Aigbogun, Omozojie P; Nwabufo, Chukwunonso K; Owens, Madeline N; Allen, Kevin; Lee, Jeremy S.; Phenix, Christopher P.; Krol, Ed S.

doi:10.1080/00498254.2022.2140315

Cited by 1 publication

(4 citation statements)

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“…To further understand the in vivo parameters of C8-6-I and 19 F-C8-6-I, we measured and reported the unbound intrinsic clearance, CLint, in mouse liver microsomes and extrapolated to predict in vivo clearance in mouse plasma, CLp using the well-stirred model. We reported a predicted CLp of 36.0 ml/min/kg for 19 F-C8-6-I compared to 34.3 ml/min/kg for C8-6-I [31]. These metabolic stability studies indicated that similar metabolites were observed in mouse, rat and human microsomes, suggesting that mice and rats are appropriate models for future animal studies of 18 F-C8-6-I.…”

Section: Discussionmentioning

confidence: 58%

“…In addition, previous studies with C8-6-I and 18 F-C8-6-I indicated that these compounds were promising as CNS PET tracers [11,31]. We previously determined that C8-6-I directly interacted with α-Syn in vitro and rescued yeast cells from α-Syn fibrillation mediated toxicity [10].…”

Section: Discussionmentioning

confidence: 95%

“…The CNS MPO score for 18 F-C8-6-I was calculated as 4.2. Based on these initial results from binding studies with isothermal titration calorimetry and in vitro yeast assay indicating binding to α-Syn [10], in vitro metabolic studies [11], kinetic measurement and pharmacokinetic predictions [31], and CNS MPO desirability score, we synthesized 18 F-C8-6-I for in vivo evaluation in healthy mice. We found that 18 F-C8-6-I was distributed in the brain regions, including the hippocampus and midbrain, which supports the reduced α-Syn expression and aggregation and neurodegeneration observed in these regions.…”

Section: Discussionmentioning

confidence: 99%

“…F-C8-6-I exhibited a moderate CNS multiparameter optimization (MPO) score (4.2), reasonable topological surface area (68.25 Å) and proper lipophilicity (cLogP: 3.46 and cLogD: 1.26)[31]. However,18 F-C8-6-I has a high molecular weight (455.57) and high pKa (9.49).…”

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confidence: 99%

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The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioural Deficits After Chronic Stimulation of Adenosine A1 Receptors

Jakova,

Aigbogun,

Moutaoufik

et al. 2024

Preprint

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We previously found that chronic adenosine A1 receptor stimulation with N6-Cyclopentyladenosine increased α-synuclein misfolding and neurodegeneration in a novel α-synucleinopathy model, a hallmark of Parkinson’s disease. Here, we aimed to synthesize a dimer caffeine-indan linked by a 6-carbon chain to cross the blood-brain barrier and tested its ability to bind α-synuclein, reducing misfolding, behavioural abnormalities, and neurodegeneration in our rodent model. Behavioural tests and histological stains assessed neuroprotective effects of the dimer compound. A rapid synthesis of the 18F-labelled analogue enabled Positron Emission Tomography and Computed Tomography imaging for biodistribution measurement. Molecular docking analysis showed that the dimer binds to α-synuclein N- and C-termini and the non-amyloid-β-component (NAC) domain, similar to 1-aminoindan, and this binding promotes a neuroprotective α-synuclein “loop” conformation. The dimer also binds to the orthosteric binding site for adenosine within the adenosine A1 receptor. Immunohistochemistry and confocal imaging showed the dimer abolished α-synuclein upregulation and aggregation in the substantia nigra and hippocampus, and the dimer mitigated cognitive deficits, anxiety, despair, and motor abnormalities. The 18F-labelled dimer remained stable post-injection and distributed in various organs, notably in the brain, suggesting its potential as a Positron Emission Tomography tracer for α-synuclein and adenosine A1 receptor in Parkinson’s disease therapy.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioural Deficits After Chronic Stimulation of Adenosine A1 Receptors

Jakova,

Aigbogun,

Moutaoufik

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

An HPLC-UV validated bioanalytical method for measurement of in vitro phase 1 kinetics of α-synuclein binding bifunctional compounds

Cited by 1 publication

References 50 publications

The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioural Deficits After Chronic Stimulation of Adenosine A1 Receptors

The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioural Deficits After Chronic Stimulation of Adenosine A1 Receptors

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