Supplement Title: Synthesis of Novel PET Radiotracers for Imaging in Alzheimer?s Disease and Related Disorders Abstract Alzheimer?s disease and related dementias (ADRD) represent a significant socioeconomic burden in the 21st Century. Worldwide, around 50 million people have dementia, and there are nearly 10 million new cases every year. In 2017, Alzheimer's cost the United States $259 billion and, by 2050, costs associated with dementia could be as much as $1.1 trillion. Fighting ADRD is therefore a high priority for the United States government and the NIH. Positron emission tomography (PET) imaging has revolutionized ADRD research. For example, PET radiotracers targeting misfolded proteins (e.g. amyloid-b, tau, and, very recently, a-synuclein) as well as neuroinflammatory pathways have provided a wealth of information on the mechanisms underpinning ADRD. These PET radiotracers enrich enrollment in clinical trials and have enabled real-time monitoring of response to therapy. They have also proven invaluable in the pursuit of effective treatments for ADRD. This progress has established the benefits of using PET radiotracers to support ADRD research and drug discovery, and created a compelling case for synthesizing new radiotracers for other targets in ADRD that cannot currently be imaged with PET. This Supplement builds on an existing collaboration between the physical sciences (Chemistry, Sanford) and life sciences (Radiology/Medical Imaging, Scott) at the University of Michigan that is supported by the parent R01 grant, and brings their collective expertise to bear on the synthesis of novel PET radiotracers for imaging ADRD. The overall objective of this Research Supplement is to address the critical need for new ADRD PET radiotracers by using the new nucleophilic radiofluorination methods being developed by Sanford and Scott to synthesize radiotracers for misfolded proteins, neuroinflammation, tyrosine kinases, and cholesterol metabolism. Radiotracers for these targets will be accessed through a variety of innovations, including: (a) identification of potential radiotracers for new ADRD targets including: misfolded proteins (TDP43 and huntingtin), neuroinflammation (CSF1R), tyrosine kinases (Tyk2), and cholesterol metabolism (cholesterol and ACAT1); (b) the development of novel transition metal-mediated methods for the nucleophilic radiofluorination of bioactive molecules (including new methods for 18F-fluorination of C-H and C-I bonds); and (c) the translation of these methods to clinically validated radiosyntheses (automated synthesis of cGMP-compliant clinical doses). Overall, this Supplement will deliver new methods for synthesizing 18F-labeled radiotracers and validated clinical syntheses of novel radiotracers for ADRD. These synthetic methods will make the new radiotracers broadly available for the ADRD community to evaluate as imaging biomarkers in preclinical work, and for potential translation into human use for clinical imaging. Both of these deliverables will expand the utility of PET imaging in ADRD research and drug discovery.
Worldwide, around 50 million people have Alzheimer?s disease and related dementias (ADRD), and there are nearly 10 million new cases every year. In 2017, Alzheimer's cost the United States $259 billion and fighting ADRD is therefore a priority for the US government and the NIH. Positron emission tomography (PET) imaging is a medical imaging technique that allows real-time in vivo monitoring of physiological processes via administration of a radiotracer (a bioactive molecule tagged with a positron-emitting radioisotope) to a patient. PET has revolutionized ADRD research because it is used for disease diagnosis, confirmation of eligibility for clinical trials, monitoring response to therapy, and supporting ADRD drug discovery. However, the impact of PET on ADRD research progress is currently limited to facets of the disease for which there are available PET radiotracers. Thus, there is an urgent need for the development of new radiotracers for other aspects of ADRD that cannot currently be imaged. The overall objective of this research supplement is to use new radiofluorination methods being developed in the parent grant to synthesize PET radiotracers for novel targets in dementia, and make them available to the ADRD community: (a) misfolded proteins; (b) neuroinflammation; (c) tyrosine kinases, and (d) cholesterol metabolism. !!
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