Development of sensitive PET tracers of pan-Amyloid-beta species for Alzheimer's disease

Massachusetts General Hospital, Boston MA

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Abstract

The recent FDA approval of Leqembi (Lecanemab) for Alzheimer’s disease (AD) has spurred great optimism, and this approval also likely opens a door for preventive treatment for AD. However, currently available PET tracers have limited capacity for this preventive purpose. More sensitive new PET tracers are highly desirable. Amyloid beta (A), is an appealing AD biomarker, as significant initial deposits of A precede Tau pathology. Accordingly, the 2018 A/T/N Research Framework published by NIA-AA (National Institute of Ageing and Alzheimer’s Association) suggests that As are the earliest biomarkers for AD before the appearance of irreversible neurologic syndromes. A species can be categorized into soluble and insoluble species. Studies show that soluble Aβs, such as oligomers, are more neurotoxic than insoluble deposits (fibrils and plaques) and serve as biomarkers for pre- symptomatic stages of AD. In fact, abnormal A levels in brains appear 30 years before symptoms are observed in humans. Unfortunately, the first-generation (1stG) A PET probes are insensitive and only marginally detect abnormal A deposits ~ 5 years before clinical AD syndrome diagnosis. This leaves a 25-year gap for which AD will progress undetectable. The intrinsic limitation of the 1stG PET tracers is their insensitivity to soluble As, the best biomarker for pre-symptomatic AD. Preliminary results from the PI’s group over the past ten years suggest that this intrinsic limitation can be overcome with CRANAD-Xs, a series of probes capable of detecting not only insoluble Aβs but also soluble Aβs in vitro and in vivo. In this application, we propose to adapt our fluorescent CRANAD-X probes into sensitive Aβ PET tracers to fill the 25-year gap. Expected long-term impact. The proposed A PET tracers will allow more sensitive detection vs. 1stG PET tracers and consequentially allow identification of AD patients at an earlier pre-symptomatic stage that is likely more responsive to treatment.