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

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 [(18)F]-radiolabeled counterpart ([(18)F]Amylovis), the in silico and in vitro comparative evaluations of [(18)F]Amylovis and [(11)C]Pittsburg compound B (PIB) and the in vivo preclinical evaluation of [(18)F]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 (18)F-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 simula-tion study the ligand-Aβ peptide complexes are stable in simulation-time (ΔG = -5.31 kcal/mol). [(18)F]Amylovis was obtained with satisfactory yield, high radiochemical purity and specific activity. The [(18)F]Amylovis log P(oct/PBS) value suggests its potential ability for crossing the blood brain barrier (BBB). According to in vitro assays, [(18)F]Amylovis has an adequate stability in time. Higher affinity to Aβ plaques were found for [(18)F]Amylovis (K(d) 0.16 nmol/L) than PIB (K(d) 8.86 nmol/L) in brain serial sections of 3xTg-AD mice. Biodistribution in healthy mice showed that [(18)F]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 [(18)F]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 [(18)F]Amylovis should be studied as a promissory PET imaging agent to detect the presence of Aβ senile plaques.