Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Parkinson disease with dementia (PDD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and psychiatric disorders significantly affect essential daily activities for millions worldwide.  To allow stratification of subjects who could benefit from a given mode of a therapeutic treatment, interrogate mechanistic pathways, and determine biomarker specificity including therapeutic efficacy, noninvasive imaging deploying a PET tracer offers a versatile investigative tool.  However, designing PET tracers capable of traversing the blood-brain barrier (BBB) to permeate brain (at sufficiently high concentrations) for allowing molecular imaging of CNS targets has been a challenging task.  Given that an imaging agent incorporated with a short-lived isotope is also expected to demonstrate critical pharmacological traits (Bmax > 10, high affinity Kd <5-10 nM, insignificant radiolysis, low nonspecific binding (NSB), absence of competing radiometabolites) as well as meet ideal radiochemistry metrics.  Therefore, PET tracer development programs encounter obstacles of immense proportion due to high attrition rate associated with CNS targeted molecular imaging agents. Although Lepinski’s rule of 5 still holds good in the ligand design, recent advent of artificial intelligence (AI) coupled with machine learning tools have revolutionized the drug development in the pharmaceutical industry. These studies provide a guiding principle for generating quantitative relationships between drug penetration and pharmacophore properties, such as molecular weight, polar surface area, and partition coefficients. Some of these key aspects for determining ability of a given pharmacophore to penetrate BBB in context of designing new PET tracers for CNS will be covered in this tutorial.   

Presenter Biography:
Dr. Sharma is a professor in departments of Radiology, Neurology, and Biomedical Engineering in Mallinckrodt Institute of Radiology (MIR), School of Medicine, Washington University in St. Louis. He is a director of T32 Postdoctoral training program in Translational Imaging in Radiopharmaceutical Sciences and Summer Research Program at the MIR. He is also a Distinguished Investigator in the Academy for Radiology and Biomedical Research. As the NIH-funded principal investigator over last 27 years at the institution, his research program is focused on the design, validation, development, and translation of PET tracers for biomedical imaging research. He has co-authored numerous patents and research publications in high impact journals and is the lead inventor of Galmydar, Fluselenamyl, and Galuminox. While Galmydar (mitochondrial viability tracer) and Fluselenamyl (Molecularly Specific Aβ tracer) are undergoing human studies at the institution, Galuminox is well on its way into the developmental pipeline for imaging inflammation.

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