Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

Abstract

SummaryThe number of people suffering from Alzheimer’s disease (AD) is expected to increase dramatically in the coming years, placing a huge burden on society. Current treatments for AD leave much to be desired, and numerous research efforts around the globe are focused on developing improved therapeutics. 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. 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. 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. Several probes discussed herein show particularly promising results and will be of immense value moving forward in the fight against AD.

Evaluation of [11C]TAZA for amyloid β plaque imaging in postmortem human Alzheimer's disease brain region and whole body distribution in rodent PET/CT

“…There has been continued interest in the development of Ab plaque imaging agents that are labeled with fluorine-18 and which may provide a higher target to nontarget ratio (Cai et al, 2007;Mathis et al, 2012;Ni et al, 2013;Verhoeff et al 2008;Zhu et al, 2014). Table I describes agents for imaging plaques some of which were recently approved by FDA, although there have been many more promising agents under development (Eckroat et al, 2013;Tu et al, 2015;Vandenberghe et al, 2010). With increasing efforts to find treatments and cure for AD, there is much research into imaging plaques and NFT essential to the diagnosis and clinical management of AD (Ariza et al, 2015;Barten and Albright, 2008;Schenk et al 1999;Verhoeff, 2007;Zimmer et al, 2014).…”

What amyloid ligands can tell us about molecular polymorphism and disease

“…Neurodegenerative diseases involving misfolded protein pathology, especially Alzheimer’s disease (AD), have been a focus of new ligand development because such agents could provide useful information on the presence of disease in a relatively inaccessible body compartment, thereby enabling the early detection and longitudinal monitoring of the pathogenic process (Vlassenko, et al, 2012). A multitude of small molecule probes have been prepared and tested for affinity and specificity in vitro , with a much smaller number moving into testing in vivo for binding potential (reviewed in (Eckroat, et al, 2013)). The great majority have been directed at the Aβ peptide or at the microtubule-associated protein tau, which form the pathognomonic lesions of AD: senile (Aβ) plaques and neurofibrillary tangles, respectively.…”

Gallium-68 radiotracers for Alzheimer’s plaque imaging

“…The scaffolds used are: chalcone, aurone, stilbene and oxadiazole, thioflavin-T, benzofuran and naphthalene. However, the most common radiolabelled probes in PET/SPECT are using 11 C and 18 F at this moment [46]. Gallium-68 is a promising radionuclide for in vivo imaging of β-amyloid plaques because it is easily produced by a generator.…”