Development of diagnostic, therapeutic, and multi-purpose agents for Alzheimer's disease

Terpstra, Karna

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https://hdl.handle.net/2142/129881 Copy

Description

Title

Development of diagnostic, therapeutic, and multi-purpose agents for Alzheimer's disease

Author(s)

Terpstra, Karna

Issue Date

2025-07-16

Director of Research (if dissertation) or Advisor (if thesis)

Mirica, Liviu M

Doctoral Committee Chair(s)

Mirica, Liviu M

Committee Member(s)

• Chan, Jefferson
• Murphy, Catherine J
• Silverman, Scott K

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Alzheimer's disease
• PET imaging
• iridium complexes
• multifunctional compounds

Abstract

Alzheimer’s disease is a progressive neurodegenerative disease that, despite discovery in the early 20th century, remains incurable. Additionally, the pathology of the disease remains unknown with many neurological abnormalities including amyloid-β plaques, phosphorylated tau neurofibrillary tangles, neuronal signaling abnormalities, increased metal ion concentrations, reactive oxygen species, and neuroinflammation all having been indicated in the progression of the disease. Among the earliest and most characteristic biomarkers of Alzheimer’s disease is the presence of amyloid-β peptide aggregates, making them an area of great interest for diagnostic agent development. Positron emission tomography agents incorporating 64Cu have been of great interest due to the long half and relatively simple incorporation by chelation of the radionuclide. In the second chapter of this work, a series of amyloid-β targeting, 64Cu chelating imaging agents were synthesized. Analysis of the complexes concluded that the presence of phenolates and carboxylic acids on the ligand increased the complex stability, but the presence of alkyl substituents close to the chelation site of the radionuclide detrimentally impacted both the stability and the lipophilicity of the complexes. This indicates that the addition of alkyl substituents close to the site of radionuclide chelation is not a beneficial tactic in increasing the lipophilicity and therefore the brain uptake of the complexes. Agents that impact the aggregation pathway of amyloid-β are of great interest for therapeutic agents and for the investigation of Alzheimer’s disease pathology. Iridium complexes have great potential in the alteration of amyloid-β aggregation pathway due to their biocompatibility, optical properties, and modular synthesis. In the third chapter of this work, a series of amyloid-β interacting Ir(III) complexes were synthesized and evaluated for their ability to enter the brain and impact the aggregation pathway of amyloid-β. HN-1, a complex with two open coordination sites was seen to significantly prevent the formation of amyloid-β plaques, likely due to the interaction of Ir(III) with amyloid-β residues. While quantification of Ir(III) complex brain uptake was hindered by solubility and likely limited blood brain barrier permeability, several complexes were shown to be present in the brains of 5xFAD mice and interact with amyloid-β. Therefore, Ir(III) complexes are promising agents for altering the aggregation pathway of amyloid-β. Several small molecule therapies are currently utilized in the clinic as Alzheimer’s disease treatments. However, the efficacy of these therapies can decrease over time and result in the side effect incidence outweighing the benefits of the therapy. Targeting donepezil and memantine therapies to the area of amyloid-β plaques may increase the efficacy of the therapies and decrease the prevalence of side effects. In the fourth chapter of this work, novel derivatives of memantine and donepezil were synthesized and evaluated as dual-function compounds. The donepezil derivatives were observed to have low inhibition capacity, indicating the mechanism of multifunctionality detrimentally impacted the interaction of the donepezil with acetylcholinesterase. However, the memantine derivative was observed to have prodrug activity, breaking down to release memantine in the brains of 5xFAD mice. Therefore, the development of donepezil derivatives by this mechanism was not beneficial, but the continued optimization of a dual-function memantine prodrug may elongate the treatment efficacy of memantine. Overall, the development and thorough understanding of agents to alter the aggregation pathway, image, and target treatments to the protein contribute to the understanding of the role amyloid-β aggregates in Alzheimer’s disease.

Graduation Semester

2025-08

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/129881

Copyright and License Information

Copyright 2025 Karna Terpstra

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