PET Radiotracer [18F] L2-b Binding to Amyloid-Beta Aggregates via Biometal Chelation within Human Cortical Brain Tissue
Sypniewski, Jacob W. J.
Pharmaceutical companies are continuing the quest for effective therapeutics to monitor the spread of Alzheimer’s Disease (AD). Since definitive diagnoses of AD were confirmed post-mortem historically, the use of clinical biomarkers that target amyloid beta (Aß) plaques has emerged as a viable method to detect the disease. To do so, clinicians have utilized a positron emission tomography (PET) imaging/radiotracer tandem to visualize the regions of interest. However, low diagnostic accuracy for AD has been indisputable, due to undesired non-specific white matter binding of the current generation of radiotracers. As such, discovery and optimization of a radiotracer that minimizes non-specific binding are paramount to improve the diagnostic accuracy. [18F] N1,N1-Dimethyl-N4-(pyridin-2-ylmethyl) benzene-1,4-diamine ([18F]L2-b, [18F]5) was previously identified as a novel PET radiotracer with high affinity towards Aß aggregates, suspected to interact with the plaques through divalent biometal chelation. However, the exact mechanism of the binding has yet to be confirmed. In this study, the PET radiotracer [18F]L2-b ([18F]5) was synthesized and biologically evaluated through displacement studies with a non-chelating analogue (4) to compare Kd/Bmax of [18F]5 to previously calculated parameters of [18F]5 in tissue alone. This will help determine the selectivity of the tracer in relation to current Aß radiotracers, which will help deduce the exact binding interaction with the tissue. We then sought to radiofluorinate the nonchelating analogue, which resulted in a low-yield product. In summary, [18F]5 binds to grey matter only slightly more than white matter, suggesting further refinement of the PET radiotracer.
ix, 38 p.
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