Poly (ADP-ribose) polymerase ligand discovery for Alzheimer's disease - Project Summary. Dysregulation of poly(ADP-ribose) polymerase-1 (PARP1) has been implicated in various neurological disorders and neurodegenerative diseases, including Alzheimer’s disease (AD) and related dementias, extending beyond its well-known application in oncology. PARP1 not only co-localizes with tau and Aβ in the brains of AD patients, but also play a pivotal role in the microglia activation and TNFα release. Therefore pharmacological modulation of PARP1 represents an attractive therapeutic approach for AD treatment. Positron emission tomography (PET) is capable of quantifying biochemical processes in vivo, and a suitable PARP1 ligand would substantially improve our understanding of PARP1-mediated cell death signaling pathway under different CNS disorders, otherwise inaccessible by ex vivo (destructive) analysis. Quantification of PARP1 in the living brain by PET would provide the assessment of distribution, target engagement and pharmacodynamic response of novel PARP1-targeted neurotherapeutics. To date, no successful examples have been demonstrated to image PARP1 in the human brain, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to develop a novel PARP1-selective brain penetrant PET ligand that can fill this void, as the first translational imaging tool. We are among the first groups to develop PARP1-specific ligands for non-oncology PET imaging applications, including the first PARP1-selective ligand [18F]PA-823. However, this ligand was discontinued due to low-to-moderate brain penetration in rodents. In our 2nd generation, we identified a lead molecule, PA-917, which showed high binding affinity and excellent selectivity. An 18F-isotopologue of PA-917 was synthesized and preliminary PET imaging studies confirmed that we have overcome the two major obstacles for PARP1-specific ligand development by achieving: 1) substantially-improved brain penetration (≥1 SUV brain uptake) and 2) high target specificity. Though PA-917 is a promising lead molecule for the development of new PARP1-targeted PET ligands, we are not clear if it is satisfactory for PET kinetics and quantification in cross-species study for clinical translation. Further optimization for balanced binding specificity and proper brain kinetics are sought for cross-species imaging studies to achieve optimal PARP1 quantification for human use. On the basis that PA-917 serves a validated lead for medicinal chemistry optimization, as specific goals, we will design and prepare a focused library of PARP1-specific modulators with balanced binding affinity and brain kinetics, as well as amenable for radiolabeling. We will evaluate their ability to quantify PARP1 expression 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 successful brain penetrant PARP1-specific PET ligand for the observational/mechanistic study of neurodegenerative disease-related biological process, but also ultimately, via PET imaging validation in higher species, to advance this ligand for potential clinical translation and monitor target response and safety margins of novel AD neurotherapeutics.
