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[18F]Amylovis as a Potential PET Probe for β-Amyloid Plaque: Synthesis, In Silico, In vitro and In vivo Evaluations

[ Vol. 12 , Issue. 1 ]

Author(s):

Suchitil Rivera-Marrero, Laura Fernández-Maza, Samila León-Chaviano, Marquiza Sablón-Carrazana, Alberto Bencomo-Martínez, Alejandro Perera-Pintado, Anais Prats-Capote, Florencia Zoppolo, Ingrid Kreimerman, Tania Pardo, Laura Reyes, Marcin Balcerzyk, Geyla Dubed-Bandomo, Daymara Mercerón-Martínez, Luis A. Espinosa-Rodríguez, Henry Engler, Eduardo Savio* and Chryslaine Rodríguez-Tanty*   Pages 58 - 71 ( 14 )

Abstract:


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.

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.

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.

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.

Keywords:

Alzheimer's disease diagnosis, positron emission tomography, β-amyloid probe, fluorine-18, iron cross-coupling reaction, docking and dynamic simulations.

Affiliation:

Department of Neurochemistry, Cuban Center for Neurosciences, Havana, Centro Nacional de Aceleradores, Parque Cientifico y Tecnologico Cartuja, Seville, Department of Neurochemistry, Cuban Center for Neurosciences, Havana, Department of Neurochemistry, Cuban Center for Neurosciences, Havana, Department of Neurochemistry, Cuban Center for Neurosciences, Havana, Center of Isotopes (CENTIS), Mayabeque, Center of Isotopes (CENTIS), Mayabeque, Radiopharmacy R&D, Uruguayan Center of Molecular Imaging (CUDIM), Montevideo, Radiopharmacy R&D, Uruguayan Center of Molecular Imaging (CUDIM), Montevideo, Radiopharmacy R&D, Uruguayan Center of Molecular Imaging (CUDIM), Montevideo, Radiopharmacy R&D, Uruguayan Center of Molecular Imaging (CUDIM), Montevideo, Centro Nacional de Aceleradores, Parque Cientifico y Tecnologico Cartuja, Seville, Department of Neurochemistry, Cuban Center for Neurosciences, Havana, Department of Neurochemistry, Cuban Center for Neurosciences, Havana, Center of Genetic Engineering and Biotechnology (CIGB), Havana, Radiopharmacy R&D, Uruguayan Center of Molecular Imaging (CUDIM), Montevideo, Radiopharmacy R&D, Uruguayan Center of Molecular Imaging (CUDIM), Montevideo, Department of Neurochemistry, Cuban Center for Neurosciences, Havana

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