Year: 2021
Type: dissertation
Abstract: Early detection of neurodegenerative diseases (NDs) has remained challenging for clinicians. To improve diagnostic confidence across the ND spectrum, there is considerable research devoted to the discovery of potential biomarkers of disease onset and progression. NDs share the common feature of progressive loss of structure and function of neurons resulting from different protein aggregates responsible for the various diseases. Alzheimer’s Disease (AD), the most prevalent ND, is characterized by amyloid plaques (composed of amyloid ß (Aß) protein) and neurofibrillary tangles (composed of tau protein) within the hippocampal and cortex regions of the brain. Parkinson’s Disease (PD), the second most common ND, is caused by dopaminergic neuronal loss within the basal ganglia, which controls voluntary movement, as a result from α-synuclein (α-syn) aggregation within the same region. Biologically relevant transition metals such as iron, copper, and zinc are reportedly accumulating and causing the aggregation of known neurotoxic protein aggregates at sites afflicted by neurodegenerative diseases. Detecting such metal ions may provide a means of early detection of these otherwise hard to diagnose diseases using positron emission tomography (PET) imaging agents. Radiopharmaceuticals available today for imaging of the central nervous system (CNS) are limited to those imaging the mid- to late-stages of CNS disease progression. This imaging modality provides information at the molecular level of living organisms that clinicians can use to confirm a diagnosis or assess the effectiveness of a treatment. Small molecules, peptides, and large proteins can be radiolabeled with a wide range of positron emitting isotopes with various half-lives such as carbon-11 (C-11, 11C, t1/2 = 20 min) and fluorine-18 (F-18, 18F, t1/2 = 109.7 min). The overall objective of the work described in this thesis is to design and analyze novel PET tracers ([11C]deferiprone (Chapter 2) and [18F]FL2-b (Chapter 3)) that bind physiological transition metals (Cu, Zn, and Fe) which are hypothesized to accumulate abnormally in the brain early in NDs. Known metal chelators will be radiolabeled and used in preclinical animal studies to determine brain uptake, binding kinetics, metabolism, biodistribution, and be evaluated in both diseased brains and healthy controls. Additional work described includes development of a novel radiotracer, [11C]AZ683, for neuroinflammation imaging (Chapter 4), where it is thought that inflammation is a result of toxic metal accumulation. Lastly, although several PET tracers are approved by the Food and Drug Administration, some of them are challenging to synthesize for routine production. Efforts to improve the synthesis of such a tracer ([18F]FDOPA) using copper-mediated radiofluorination in accordance with current good manufacturing processes (cGMP) are also discussed (Chapter 5).
DOI: 10.7302/1411
Author: Tanzey, Sean
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4287405441