Recent Advances in the Development of Amyloid Imaging Agents

Abstract

Excessive amyloid-beta (Abeta) deposition in the brain is one of the most crucial events in the early pathological stage of Alzheimer's disease (AD). Therefore, Abeta deposits have enough potential to become a useful biomarker for not only an early diagnosis of AD, but also for the assessment of the clinical efficacy of anti-Abeta therapies, if they can be measured non-invasively and reliably in living patients. As a potent candidate technique to measure this biomarker, PET amyloid imaging using a radioligand for Abeta deposits has received much attention. A large number of Abeta ligands have been synthesized and evaluated as candidates for amyloid imaging agents. These can be classified into six categories of derivatives: Congo-red, Thioflavine T, stilbene, vinylbenzoxazole, DDNP, and miscellaneous. Many of these derivatives exhibit high binding affinities to Abeta fibrils (below 20 nM) and some of them also show excellent brain pharmacokinetic profiles. The concept of amyloid imaging is currently being tested in human PET studies using optimized amyloid imaging agents. Despite the small number of subjects, these studies have demonstrated sufficiently promising results. This review article provides an overview of recent advances in the development of amyloid imaging agents, and includes: a summary of the fundamental basis and clinical significance of amyloid imaging; lists of binding affinity data for 135 compounds classified into 12 molecular frameworks; a comprehensive discussion of the in vitro and in vivo features of representative Abeta ligands; and a discussion of the current state of clinical evaluation of these amyloid imaging agents (PIB, SB-13, BF-227, and FDDNP).

Novel 18F-Labeled Arylquinoline Derivatives for Noninvasive Imaging of Tau Pathology in Alzheimer Disease

“…The optimization of pharmacokinetics is an important aspect in the development of a PET tracer (38). 18 F-THK-5105, 18 F-THK-5116, and 18 F-THK-5117 fulfilled the criteria of appropriate log P value (log P 5 1-3) for brain entry (39).…”

Binding Modes of Thioflavin-T to the Single-Layer β-Sheet of the Peptide Self-Assembly Mimics

“…1,2 ThT's fluorescence emission is dramatically enhanced upon fibril binding, which makes ThT particularly useful in real-time detection of fibrils. ThT does not typically bind to monomeric proteins but appears to recognize and bind to some inherent structural features of amyloid fibrils.…”

Voxel-Based Analysis of Amyloid Positron Emission Tomography Probe [¹¹C]BF-227 Uptake in Mild Cognitive Impairment and Alzheimer’s Disease

“…Several small molecular amyloid-binding agents have been designed for monitoring amyloid deposits in patients with MCI and AD and for evaluating the efficacy of antiamyloid therapy [8][9][10][11][12] . Furthermore, we have developed several benzoxazole derivatives as potential candidates for amyloid PET probes [13,14] .…”