Evaluation of F-18 Labeled Hydroxy Quinoline Derivative as a Potential PET Imaging Agent for Early Detection of Alzheimer’s Disease
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Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive cognitive decline in the elderly people older than 65 years of age. The pathological hallmarks of the disease include extracellular senile plaques and intracellular tangles developing during the pre-symptomatic stage. Although the definite diagnosis of AD is only possible post-mortem, non-invasive imaging has provided an important tool for early detection, and has helped in planning for an effective treatment. Targeted molecular imaging using positron emission tomography (PET) has provided the insight into understanding different disease mechanisms with high sensitivity. Based on the amyloid cascade hypothesis, congo red and thioflavine derivatives have been investigated as potential PET ligands that bind specifically to the amyloid plaques. Another hypothesis, the metal hypothesis, suggested that elevated level of metals particularly zinc, copper and iron, can interact with amyloid beta proteins to form metal complexes. The use of metal chelation therapy has emphasized the involvement of metals in the aggregation of plaques and has shown promising results in clinical and animal studies through dissolving plaques and restoring the metals balance in the affected brains. In this study, based on the metal hypothesis, 18F-labeled 8-hydroxy quinoline was investigated as a potential PET imaging agent for early detection of AD in APP/PS1 mouse model. This agent demonstrated high binding affinity to the plaque aggregates (1.5 nM), and increased fluorescence intensity upon binding to zinc. In addition, in vivo studies showed the feasibility of differentiating mice with AD from normal control mice (p < 0.05), and the ability to detect different plaque densities at different ages of AD (4, 6, and 12 months). Good correlations were found between autoradiography, histology and PET images. The biodistribution data demonstrated rapid uptake and clearance of this compound in the normal brain of wild-type mice.