![]() In this review, we provide an overview of these AD radiolabeled early-diagnostic probes according to their scaffolds, with a special emphasis on their synthesis as well as their structure–activity and brain-kinetics relationships. The scaffolds from which these newer radiolabeled probes are derived include chalcone ( 5) and its conformationally restricted analogues flavone ( 6) and aurone ( 7) stilbene ( 8) and its analogues diphenyl-1,2,4-oxadiazole ( 9) and diphenyl-1,3,4-oxadiazole ( 10) and thioflavin-T analogues such as benzothiazole ( 11), benzoxazole ( 12), benzofuran ( 13), imidazopyridine ( 14), and benzimidazole ( 15) as well as quinoline ( 16) and naphthalene ( 17) derivatives ( Figure 1B). During the past decade, efforts directed at developing probes that display uptake and retention that differ in healthy and AD-affected brains resulted in a variety of radiolabeled molecular probes for in vivo PET/SPECT imaging. However, the bulky and ionic natures of these dyes prevented them from crossing the blood brain barrier (BBB), and consequently, no in vivo benefits were obtained from these initial investigations. Early efforts towards developing Aβ stains focused on dyes such as congo red ( 1), chrysamine G ( 2), pinacyanol ( 3), and thioflavin-T ( 4) ( Figure 1A). To provide a high readable signal-to-background ratio, the ideal Aβ-imaging probes should have certain brain kinetics: a rapid initial brain uptake and a fast washout. ![]() The presence of different binding sites in Aβ aggregates led medicinal chemists to investigate and develop a variety of chemical scaffolds as Aβ-imaging tracers. Therefore, as Aβ plaques precede the onset of dementia and cognitive decline in AD patients, their detection by nuclear imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) represents the presymptomatic diagnostic tool of choice for AD. Obviously these kinds of diagnostic tools lack absolute sensitivity and accuracy, especially in the early stages of the disease. In view of the limited accessibility to living brain and other central nervous system (CNS) tissues, AD is currently diagnosed through memory tests and/or based on the patients’ history. Postmortem histopathological examination of Aβ plaques is currently the only way to firmly confirm AD. However, the exact cause of AD still remains unknown. Observations of these hallmarks have led to several hypotheses in attempts to explain the underlying cause of the disease, which is likely multifactorial. Several pathological hallmarks of AD have been identified, and they include decreased cholinergic neurons and acetylcholine (ACh) levels, plaques caused by aggregation of the protein fragment amyloid-β (Aβ), tangles associated with irregular phosphorylation of tau protein, inflammation and increased oxidative stress from reactive oxygen species (ROS), as well as dyshomeostasis and miscompartmentalization of metal ions such as Cu, Fe, and Zn. As these numbers indicate, AD represents a significant and increasing burden on our population, and efforts towards the development of new and improved diagnostics and therapeutics for this devastating disease are important research endeavors. Between 20, the number of deaths caused by AD increased by 66%, a dramatic rise, especially when compared to other causes of death, such as heart disease, stroke, prostate and breast cancer, and HIV, which decreased by 3–29% during that time period. In the United States, AD represents the 6th leading cause of death. Several probes discussed herein show particularly promising results and will be of immense value moving forward in the fight against AD.Īlzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system currently affecting ~5.4 million Americans, a number that could increase to 11–16 million by the year 2050. ![]() This review provides a survey of chemical probes developed to date for AD with emphasis on synthetic methodologies and structure–activity relationships with regards to affinity for target and brain kinetics. ![]() These facts have led to numerous efforts to develop chemical probes to detect pathophysiological hallmarks of AD, such as amyloid-β plaques, for diagnosis and monitoring of therapeutic efficacy. In addition, current diagnostic tools for AD rely largely on subjective cognitive assessment rather than on identification of pathophysiological changes associated with disease onset and progression. Current treatments for AD leave much to be desired, and numerous research efforts around the globe are focused on developing improved therapeutics. The number of people suffering from Alzheimer’s disease (AD) is expected to increase dramatically in the coming years, placing a huge burden on society.
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