PET Imaging of Sphingolipid Signaling: Current Radiotracers, Translational Gaps, and Opportunities in Neurodegeneration and Oncology.

Sphingolipids regulate membrane organization, cell fate, and immune signaling in both health and disease. Dysregulation of the ceramide, sphingomyelin, and sphingosine-1-phosphate (S1P) pathways contribute to neuroinflammation, neurodegeneration, vascular injury, and cancer, motivating the development of in vivo imaging approaches to quantify sphingolipid signaling. Cellular homeostasis depends on a tightly regulated balance between pro-apoptotic ceramide and pro-survival S1P. Disruption of this balance, particularly through increased sphingosine kinase 1 (SPHK1/SK1) expression has been linked to aggressive tumor phenotypes and poor clinical outcomes. Recent advances in positron emission tomography (PET) have enabled imaging of select sphingolipid targets, including ceramide transport protein (CERT) and S1P receptor 1 (S1PR1), with one tracer progressing to first-in-human studies. While sphingolipid PET imaging has been applied in Alzheimer's disease (AD) research, translation to oncology remains limited despite the key role of sphingolipid metabolism in cancer biology and therapy. This review summarizes reported sphingolipid-targeted PET tracers, highlighting their biological rationale, radiochemical development, and preclinical and clinical applications, and emphasizes opportunities to advance sphingolipid PET imaging towards cancer imaging.