This review evaluates recent advances in the development of translocator protein (TSPO) – and purinergic receptor–binding PET tracers and highlights the capacity of TSPO-PET-imaging to capture microglial activation across multiple regions of interest in multiple sclerosis brain. We discuss the added value of integrating PET-derived measures with fluid and metabolic biomarkers, as well as their successful application in recent clinical trials.

Recent research highlights PET as a robust molecular imaging tool for detecting microglial activation and implicates dysregulated microglial activity as a key driver of smouldering multiple sclerosis pathology. PET-detectable microglial activation appears not merely as a secondary response to neuroaxonal injury but is increasingly recognized as an integral inflammatory component of ongoing pathological processes that lead to future brain atrophy and clinical deterioration.

Recent advances establish PET as an essential research tool for evaluating the presence of smouldering inflammation in MS brain not detectable using MRI. Furthermore, PET-based methods have proven suitable for measuring glial responses to potentially neuroprotective therapies currently under development.