Ligand discovery for delineating cholesterol homeostasis in the brain

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Project Abstract: The PI and his investigation team at Emory aim to establish a productive and collaborative research platform and acquire advanced research skills in Japanese host institution (NIRS/QST) to support the advancement of the parent NIH award through the US-Japan Brain Research Cooperative Program (BRCP). Alzheimer’s disease (AD) is a long-term neurodegenerative disorder that ranks sixth in the leading cause of all deaths in the United States and features amyloid β protein deposition and neurofibrillary tangles. At present, there are no drugs available to halt or reverse disease progression, and all efforts to create such therapies have failed. Recent studies have demonstrated that abnormalities of cholesterol homeostasis in the brain are strongly associated with several neurodegenerative diseases, including AD. The CYP46A1 enzymatic conversion of brain cholesterol into 24S- hydroxycholesterol is the major elimination mechanism to maintain brain cholesterol homeostasis. Disturbances in CYP46A1 is implicated in the AD physiopathology. Therefore, pharmacological modulation of CYP46A1 represents an attractive AD therapeutic approach. Positron emission tomography (PET) is capable of quantifying biochemical processes in vivo, and a suitable CYP46A1 ligand would substantially improve our understanding of CYP46A1- mediated cholesterol homeostasis under AD physiopathological conditions otherwise inaccessible by ex vivo (destructive) analysis. Quantification of CYP46A1 in living AD brain by PET would provide the assessment of distribution, target engagement and dose occupancy of new AD therapeutics. To date, no successful examples have been demonstrated to image CYP46A1 for clinical use, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to develop a novel PET ligand that can fill this void, as the first translational imaging tool for AD. Through the administrative supplements for the U.S.-Japan Brain Research Cooperative Program, we will achieve our goals through the following objectives: (1) To conduct collaborative research activities in the development of PET ligands targeting CYP46A1 in the central nervous system and its implication in Alzheimer’s disease as the focus of PI’s parent award; (2) To provide a training flatform to acquire advanced research skills, such as radiochemistry and PET imaging studies, in the Japanese host institution (NIRS/QST) that could substantially benefit our existing parent research; and (3) To establish a productive and sustainable working relationship and scientific dialog between Emory and NIRS/QST for continued collaboration on mutually interested research topics that aligned with the NIA mission.