Design and synthesis of a novel PET probe for early detection of Alzheimer’s disease

Objectives While several PET tracers (PIB, Avid 45, GE-067, AZD4694) are under development, Avid45 and GE-067 (Flutemetamol) have been recently approved by FDA for Aβ imaging in Alzheimer’s disease (AD). These agents show high levels of nonspecific white matter retention and are unable to detect diffuse Aβ, a preclinical manifestation of the disease. Thus AD diagnosis at preclinical stages continues to be a challenging undertaking, and an unmet goal. To supplement an existing armamentarium of FDA approved agents, we have discovered a small fluorescent molecule that shows characteristics of translatable imaging agents, while also binding the diffuse plaques in confirmed AD tissues.

Methods The fibril binding assay, immunohistochemistry, multiphoton imaging and biodistribution in mice have been performed using established procedure.

Results The lead agent shows a concentration dependent and saturable binding with preformed Aβ1-42 aggregates (Kd=1.58±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 staining of fibrillar and diffuse plaques in the parenchymal regions of brain sections in APP/PS1 mice, and distinct labeling of diffuse as well as fibrillar Aβ plaques in the hippocampal tissue of a neuropathologically confirmed AD patient. Preliminary multiphoton real-time imaging shows ability of this molecule to traverse the blood-brain barrier and label parenchymal Aβ plaques in brains of transgenic mice within minutes post-intravenous injection.

Conclusions The lead agent demonstrates characteristic features of translatable imaging agents and provides a template scaffold for further optimization and development of Aβ-targeted probes.