Development of amyloid beta binding bifunctional chelators for diagnosis of Alzheimer’s disease

Wang, Yujue

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https://hdl.handle.net/2142/110715 Copy

Description

Title

Development of amyloid beta binding bifunctional chelators for diagnosis of Alzheimer’s disease

Author(s)

Wang, Yujue

Issue Date

2021-04-22

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

Mirica, Liviu M

Doctoral Committee Chair(s)

Mirica, Liviu M

Committee Member(s)

• Lu, Yi
• Chan, Jefferson
• Olshansky, Lisa

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Alzheimer's disease, Diagnosis

Abstract

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease and the most common cause of dementia globally. AD is the 6th leading cause of death in the United States and places a huge economic burden on healthcare. To date, there are no disease-modifying therapies for AD. The ultimate pathology of AD has not been elucidated. Among all the hypotheses proposed for the mechanism of AD, the amyloid cascade hypothesis is the most widely held. The amyloid cascade hypothesis states that the deposition of amyloid plaques, which is the characteristic pathological feature found by brain autopsy in patients with AD, is the main cause of AD. Amyloid plaques are insoluble aggregates consist of amyloid β (Aβ), a soluble peptide which main alloforms are 40 and 42 amino acid residues long. After being cleaved from amyloid precursor protein (APP) and secreted into extracellular space, Aβ is prone to self-aggregate, generating species including amyloid oligomers, fibrils, and aggregates. These neurotoxic assemblies have been targeted as the biomarkers for the diagnosis of AD using molecular imaging modalities. Positron emission tomography (PET) is a non-invasive nuclear imaging technique that allows for measuring Aβ plaques burden in vivo using radiotracers labeled with 11C (t1/2=20.4 min), 18F (t1/2= 109.7 min), and 64Cu (t1/2 = 12.7 h). Radiometal 64Cu has more favorable properties for amyloid imaging in terms of half-life and radiolabeling strategy. To obtain molecules that could be employed as 64Cu PET imaging agents and maintain affinity for Aβ species, our synthetic strategy is to covalently link 2-phenylbenzothiazole moiety, which has appreciable Aβ binding affinity and fluorescent properties, with multidentate ligands based on 1,4,7-triazacylononane (TACN). The modification of metal chelating group is centered on introducing carboxylate ester branches to TACN backbone for more favorable lipophilicity as well as metal-binding affinity. First, we designed a series of diester bifunctional chelators (BFCs) and characterize them via a series of biophysical experiments, including ex vivo transgenic mouse brain section staining and autoradiography studies for assessment of amyloid plaques targeting ability, along with 64Cu radiolabeling studies and measurement of the octanol/PBS distribution coefficient (log D) values for prediction of blood-brain barrier (BBB) permeability. YW-13 shows the best amyloid staining but suffers from the low log D value of anionic 64Cu complex. Therefore, we adapted the compound design by replacing one carboxylate arm with a methyl group. All five BFCs in this series exhibit favorable log D values around 1 and have moderate brain uptake in biodistribution studies. Next, to further improve the amyloid targeting ability of the BFCs, we attached a second amyloid binding fragment and the resultant BFCs all showed satisfying colocalization with the Aβ antibody staining signals. The lipophilicity is enhanced as well. Notably, YW-3 exhibits an elevated brain uptake in transgenic mice versus wild-type mice, and the brain uptake of 68Ga-YW-18 is twice that of 64Cu-YW-18, indicating neutral metal complexes are more favored for in vivo application. Last, we probed the metal binding affinity of hinokitiol through UV-Vis spectrophotometric titrations and synthesized Hino-TACN ligands as novel metal-chelating fragments. We also proposed the next generation BFCs as molecules that could form neutral 64Cu complexes and have smaller molecular weights than the current BFCs.

Graduation Semester

2021-05

Type of Resource

Thesis

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http://hdl.handle.net/2142/110715

Copyright and License Information

Copyright 2021 Yujue Wang

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