Human islet amyloid peptide (hIAPP1–37) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP1–37) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP1–37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP1–37. When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP1–37. Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP1–37 oligomers. The modulation of proteostasis by the family of pharmaco-chaperones A–F is a promising potential approach to limit the onset and progression of diabetes and its comorbidities.
Background: Alzheimer’s disease (AD) is the most common form of dementia. Neuroimaging
methods have widened the horizons for AD diagnosis and therapy. The goals of this work are the synthesis
of 2-(3-fluoropropyl)-6-methoxynaphthalene (5) and its [18F]-radiolabeled counterpart
([18F]Amylovis), the in silico and in vitro comparative evaluations of [18F]Amylovis and [11C]Pittsburg
compound B (PIB) and the in vivo preclinical evaluation of [18F]Amylovis in transgenic and wild mice.
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Methods: Iron-catalysis cross coupling reaction, followed by fluorination and radiofluorination steps were
carried out to obtain 5 and 18F-Amylovis. Protein/Aß plaques binding, biodistribution, PET/CT Imaging
and immunohistochemical studies were conducted in healthy/transgenic mice.
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Results: The synthesis of 5 was successful obtained. Comparative in silico studies predicting that 5
should have affinity to the Aβ-peptide, mainly through π-π interactions. According to a dynamic simulation
study the ligand-Aβ peptide complexes are stable in simulation-time (ΔG = -5.31 kcal/mol).
[18F]Amylovis was obtained with satisfactory yield, high radiochemical purity and specific activity. The
[18F]Amylovis log Poct/PBS value suggests its potential ability for crossing the blood brain barrier (BBB).
According to in vitro assays, [18F]Amylovis has an adequate stability in time. Higher affinity to Aβ
plaques were found for [18F]Amylovis (Kd 0.16 nmol/L) than PIB (Kd 8.86 nmol/L) in brain serial sections
of 3xTg-AD mice. Biodistribution in healthy mice showed that [18F]Amylovis crosses the BBB with
rapid uptake (7 %ID/g at 5 min) and good washout (0.11±0.03 %ID/g at 60 min). Comparative PET dynamic
studies of [18F]Amylovis in healthy and transgenic APPSwe/PS1dE9 mice, revealed a significant
high uptake in the mice model.
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Conclusion: The in silico, in vitro and in vivo results justify that [18F]Amylovis should be studied as a
promissory PET imaging agent to detect the presence of Aβ senile plaques.
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