S1PR-Targeted PET Imaging: Advancing Insights into Neuroinflammatory and Immune-Related Pathologies

Sphingosine-1-phosphate (S1P) and its receptors (S1PRs) are pivotal regulators of immune cell trafficking, vascular integrity, and various physiological processes, playing key roles in the pathogenesis of neuroinflammatory and immune-related disorders. Among these, multiple sclerosis (MS) is the most common chronic inflammatory condition affecting the central nervous system (CNS), marked by autoimmune-induced neurodegeneration, inflammation, and ongoing demyelination. FTY720, known as fingolimod or Gilenya, is an immunomodulatory medication that was approved in 2010 as the first oral therapy for relapsing-remitting MS. Upon phosphorylation, FTY720 mimics S1P and binds selectively to all S1PR subtypes, except S1PR2, underscoring the therapeutic possibilities of focusing on the S1P–S1PR signaling axis for neuroinflammatory conditions. This success emphasizes the relevance of S1P-mediated pathways in both disease mechanisms and treatment strategies. Emerging precision medicine approaches emphasize the importance of noninvasive imaging to elucidate molecular mechanisms in vivo . Positron emission tomography (PET) imaging–utilizing suitable radioactive tracers to probe biological targets and processes in vivo –offers a transformative approach to quantifying receptor expression, thereby delineating crucial insights into disease diagnosis, therapy monitoring, and therapeutic drug development. As such, S1PR-specific PET imaging provides a promising approach to explore the pivotal role of S1PRs in MS and other immune-mediated diseases. This review offers a comprehensive overview of the development and clinical applications of S1PR-targeted PET radiopharmaceuticals, illustrating their potential to transform therapeutic strategies. Further, recent advances in radiopharmaceutical design have yielded S1PR-targeted PET probes with high specificity, improved metabolic stability, and enhanced blood–brain barrier penetration, addressing key challenges in imaging neuroinflammation. Additionally, it critically discusses future directions for S1PR-targeted PET imaging in advancing our understanding of disease mechanisms, improving patient outcomes, and contributing to the broader vision of precision medicine.