Topic: Targeting on S1PR1 for Neuroinflammation—Moving from Bench to Bedsie
Speaker: Professor Tu Zhude, Washington University School of Medicine in St. Louis (WUSTL)
Date and time: August 12, 10:30–11:30
Venue: Room 103, BME Building
Host: Luo Zonghua
Abstract:
Sphingosine-1-phosphate receptor 1 (S1PR1) is extensively expressed on lymphocytes and endothelial cells, playing a crucial role in autoimmune inflammatory processes by regulating immune cell trafficking in the brain. Multiple sclerosis (MS) is associated with a lymphocyte-mediated autoimmune response that leads to repeated cycles of demyelination and repair. Currently, four S1P modulators have been approved by the FDA for treating MS, but the pathophysiologic mechanism of S1PR1 in MS is still not well understood. Positron emission tomography (PET) investigations into S1PR1 function in MS and other diseases are limited by the lack of a suitable radiotracer. To address this urgent need, Dr. Tu has been focusing on developing a clinically suitable PET S1PR1 radiotracer for detecting neuroinflammation in the brain associated with MS and other neurological diseases. They have designed, synthesized, and evaluated approximately 100 compounds for their binding potency and selectivity for S1PR1. Additionally, they have radiosynthesized about 20 radioligands using C-11, F-18, I-125, or H-3 isotopes and validated them in vivo in six animal models of inflammatory diseases. In 2019, they transferred [11C]CS1P1 into clinical investigation. Their clinical study data confirmed that [11C]CS1P1 is safe for human use. Their proof-of-mechanism brain studies showed higher uptake of [11C]CS1P1 in gray matter than in white matter, consistent with S1PR1 mRNA expression in the normal human brain. In MS patients, they observed increased [11C]CS1P1 uptake within both brain lesions and normal-appearing white matter (WM). These results align with existing evidence of inflammatory infiltrate in both brain lesions and normal-appearing WM in MS. Together, their data suggest that PET with an S1PR1 radiotracer can detect neuroinflammation in the brains of MS patients. Currently, they are exploring the use of [11C]CS1P1 in Alzheimer’s disease (AD), Parkinson’s disease (PD), cerebrovascular small vessel disease (CVSD), and oncology, with a total of 70 human scans completed. Additionally, they are in the process of transferring an F-18 S1PR1 radiotracer into clinical use.
Biography:
Dr. Tu Zhude is a Professor of Radiology in Washington University School of Medicine (WUSM) in St. Louis. He serves as the Director of the Precision Radiotheranosties Translation Center (PRTC) at the Mallinckrodt Institute of Radiology (MIR), WUSM. Dr. Tu received his PhD in 1995 from Beijing Normal University, China, and completed his postdoctoral training at the University of Minnesota, Minneapolis, in 2000. He has over 20 years of faculty experience at the Mallinckrodt Institute of Radiology as a PET radiochemist. His research primarily focuses on the development and validation of PET radiopharmaceuticals, translating promising candidates into clinical investigations for human use, and their implementation for patients with various diseases. While most of his team’s efforts are concentrated on neuroimaging, their research also encompasses cardiovascular and cancer imaging. His team has successfully translated 12 PET radiopharmaceuticals into clinical investigations for human use in the MIR PET program. Dr. Tu’s research has been predominantly supported by federal agencies, including the NIH, DOE, and other foundations. Recognized for his outstanding contributions to the field, Dr. Tu received the Distinguished Investigator Award from the Academy of Radiology Research in 2018. Dr. Tu is also an exceptional mentor. He has guided more than 50 young investigators, including postdocs, junior scientists, and visiting scholars. Those who have trained in his laboratory have gone on to become successful faculty members at prestigious research institutions or key figures in medical health industry corporations.