Thursday, March 20, 2025
3/20/2025
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. Our ligand [11C]CYP-507 demonstrated the first prototype for imaging towards CYP46A1, but was discontinued due to marginal binding specificity and low brain penetration. In our next generation, we successfully identified a lead molecule, CYP-812, which showed high binding affinity and high selectivity. An 11C-isotopologue of CYP-812 was synthesized and preliminary PET studies confirmed that we have overcome the major obstacles for CYP46A1 ligand development by achieving: 1) reasonable and regional-specific brain uptake; 2) moderate target specificity. Though CYP-812 is a promising lead, further optimizations aimed at higher brain permeability, improved potency and binding specificity with proper brain kinetics are sought for translational cross-species (rodents and nonhuman primates) imaging studies to achieve optimal CYP46A1 quantification for AD research. As specific goals, we will design and prepare a focused library of CYP46A1 modulators amenable for labeling with 11C or 18F, and evaluate their ability to quantify CYP46A1 activity and changes during drug challenge in rodents and nonhuman primates, as well as autoradiography and biological validation in postmortem human brain tissues. The impact of this work is not only to develop the first potent and selective CYP46A1 PET ligand for the study of AD-related biological processes, but also ultimately, via PET imaging validation in higher species, to advance this ligand for potential clinical translation and monitor target response of novel AD neurotherapeutics.
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