Novel PET tracers for molecular imaging of Alzheimer’s disease

Objectives Alzheimer's disease (AD) diagnosis at prodromal stages continues to be a challenging undertaking, and an unmet goal. Development of sophisticated neuroimaging techniques could have a profound impact on improving early diagnosis, monitoring disease progression, and assessing therapeutic response. While several PET tracers are under development, Avid45, GE-067 and AZD4694 have been recently approved by FDA for Aβ imaging. These agents show high levels of nonspecific white matter retention, low biological half lives and are unable to detect diffuse Aβ plaques, a preclinical manifestation of the disease. To supplement an existing armamentarium of FDA approved agents, we have discovered a small organic molecule that shows characteristics of translatable imaging agents to enable molecular imaging of AD.

Methods The multiphoton imaging, binding assays with fibrils and AD homogenates, biodistribution, PET imaging in mice, immunohistochemistry in mice and humans have been performed using literature procedures.

Results The novel heterocyclic agent shows a concentration dependent and saturable binding with AD homogenates (Kd=1.70±0.05nM). The F-18 counterpart demonstrates high first pass extraction into brains (8.86 % ID/g; 2 min) of normal mice, followed by clearance over 60 min. Additionally, the agent exhibits distinct labeling of fibrillar and diffuse plaques in the parenchymal region of brain sections in live APP/PS1 mice and the hippocampal tissue sections of a neuropathologically confirmed AD patient. Preliminary multiphoton real-time imaging shows its ability to traverse the blood-brain barrier and label Aβ plaques in brains of transgenic mice and blood vessels (CAA), within minutes post-intravenous injection. Compared to other neurodegenerative diseases, the agent is highly specific for AD.

Conclusions In summary, the lead agent demonstrates characteristic features of translatable imaging agents and provides a platform scaffold for further optimization and development of Aβ-targeted probes.