Blood-Brain Barrier Permeable Multimodal Imaging Agents for Neurodegenerative Diseases

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Project Summary / Abstract The aggregation of peptides and proteins plays a key role in many devastating neurodegenerative disorders, including Alzheimer's disease (AD) and other AD-related dementias (ADRD) such as Lewy Body dementia (LBD) and Frontotemporal degeneration (FTD), as well as Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Among these amyloid disorders or proteinopathies, Alzheimer's disease (AD) is the most common neurodegenerative disease and the sixth leading cause of death in United States. Around 6 million people are presently diagnosed with AD in the US, and the number is expected to reach 14 million by 2050. To date there is no disease-modifying treatment for AD and its diagnosis with high accuracy requires a detailed post-mortem examination of the brain. While the main neuropathological hallmark of AD is the deposition of amyloid plaques comprising the amyloid beta (Aβ) peptide, new therapeutic targets also include the phosphorylated tau (p-tau) aggregation, as well as reactive oxygen species (ROS) generation, neuroinflammation, and oxidative stress. Therefore, there is a huge unmet need to develop diagnostic agents that can detect at an earlier stage the formation of oligomeric aggregates of the various amyloid proteins involved in proteinopathies (such as Aβ and p-tau in AD, and α-synuclein in PD), as well as target other hallmarks of these disorders such as neuroinflammation and oxidative stress. Herein, we plan to employ a fundamental chemical approach to generate novel blood-brain barrier permeable multifunctional and dual PET/MRI imaging agents and evaluate in vivo their ability as diagnostic agents for AD and ADRD. In these studies, we will employ novel organic and inorganic chemical design principles and synthetic approaches, along with the detailed characterization of the developed bioinorganic systems for imaging/diagnostic applications. Progress in all presented research directions will lead to the development and optimization of novel diagnostic agents for advancing human health.