Development of PET radiotracer for imaging sphingosine-1-phosphate receptor 2 (S1PR2)

TR&D 1项目总结

TR&D 1 Project Summary The ultimate goal of this TR&D 1 is to develop a small molecule PET radiotracer for in vivo imaging of Sphingosine-1-phosphate receptor 2 (S1PR2) for multiple sclerosis (MS), bladder cancer, and other diseases. Sphingosine-1-phosphate (S1P) binds to a superfamily of five receptors, S1PR1-5, which play critical regulatory roles in pathophysiological processes in a variety of common human diseases. S1PR2 was first cloned from rat aortic vascular smooth muscle cells and later identified as a high affinity S1P receptor (S1PR). S1PR2 modulates various cellular signaling pathways including cell growth and survival, migration, and adhesion in inflammation, fibrosis, diabetes, and cancer. Although S1PR1 is up-regulated by activated astrocytes and myeloid cells, S1PR2 also contributes significantly to inflammation in CNS autoimmune diseases and other diseases. S1PR2 is expressed by brain endothelial cells and modulates microglial activation. In MS, infiltrates rich in immune cells are found in the meninges within highly organized structures named ectopic lymphoid follicles (ELF) that mimic secondary lymphoid organs. A key role for S1PR2 in MS is regulating the infiltration of immune cells into the meninges. Experimental autoimmune encephalomyelitis (EAE) is a rodent model of relapsing-recurring-MS (RR-MS); treatment of animals with the S1P2 antagonist JTE-013 significantly diminishes the accumulation of meningeal lymphocytes following relapses. S1PRs and their signaling pathways also play a critical role in the destiny of cancer cells. The different S1PR subtypes (S1PR1-5) have different functions in cancer. Studies of bladder cancer tissue samples showed that S1PR1/2 subtype mRNA expression level correlates with different grades and stages of bladder urothelial carcinoma, suggesting that S1PR2 could be a biomarker for bladder carcinoma; targeting S1PR2 may provide an innovative therapeutic strategy. In partnership with our Collaborative Projects (CPs) we will accomplish two specific aims in developing a C-11 or F-18 labeled S1PR2 specific PET radiotracer: 1) We will design and synthesize new S1PR2 ligands then determine their in vitro binding potency and selectivity for S1PR2; S1PR2 ligands will be radiolabeled with C-11 or F-18; 2) Biological evaluation of the radiotracers in animals including: a) studies with our CPs using rodent models of MS and a rodent model of bladder cancer, b) evaluation of both S1PR1 and S1PR2 radiotracers for autoimmune response for in rodent model of MS by a CP, c) PET brain imaging study in nonhuman primates and radiometabolite analysis of the most promising radiotracer based on feedback from our CPs. Radiolabeled precursors and cold reference compounds, and the radiochemistry protocols will be shipped to CPs and Service Projects and other entities that are interested at exploring S1PR2 radiotracers for these and other applications. Upon completion of this renewal, the most promising S1PR2 radiotracer will be ready for further dosimetry/toxicity studies prior to seeking FDA approval for human use.