Technology Research & Development Project 1

Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator. Through interacting with S1P receptors, S1P plays critical roles in physiological and pathophysiological processes of the immune system, central nervous system (CNS), and cardiovascular system. S1P receptors (S1PR1-5) are a five family members of cell-surface G protein-coupled receptors and they are expressed throughout the body. Out of the five S1P receptor subtypes, S1PR1 is expressed in cell of immune system and CNS system and it plays critical functions in inflammatory diseases which include multiple sclerosis (MS), atherosclerosis, acute and chronic liver and lung injury, diabetes, cancer, rheumatoid arthritis, inflammatory bowel disease and others. The characterization of S1PR1 is to maintain endothelial barrier function under both basal and inflammatory conditions; in addition, S1PR1 also has function of regulating immune cell trafficking during inflammatory response. Encouraged by the success of fingolimod (FTY720, Gilenya) treating relapsing-remitting MS, tremendous efforts have focused developing therapeutics targeting S1PR1. However, the pathological mechanisms by which S1P1 mediates biological processes in different diseases are not well understood. 

Positron emission tomography (PET) is a non-invasive imaging modality that is capable of providing functional information about molecular and cellular processes in living subjects. Therefore, a PET radioligand having high affinity and selectivity for S1PR1 would provide a unique methodology to investigate the change of the S1PR1 expression in inflammatory response in living subjects and study the physiological function of S1PR1 in variety of diseases. Due to the longer the half-life of F-18 (T1/2 = 109.8 min) over that of C-11 (T1/2 = 20.3 min), a clinical suitable F-18 labeled S1PR1 PET tracer will offer less time restrict for production, distribution and clinical use over C-11 labeled PET tracers. 

The goals of this project are: (1) Translate the S1P1 ligand 11C-TZ3321 into initial human evaluations for safety and efficacy, and (2) In vivo characterization of 18F-labeled new and selective tracer pharmaceutical properties in inflammatory diseases animal models.