Targeted Radiopharmaceuticals for Synovitis: Emerging Molecular Imaging and Theranostic Perspectives

The management of rheumatoid arthritis and related inflammatory arthropathies is evolving from late structural assessment toward early molecular phenotyping of synovitis. Target-specific radiopharmaceuticals for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) now permit non-invasive detection of activated fibroblast-like synoviocytes, inflammatory macrophages, chemokine-driven immune-cell trafficking, angiogenesis, and mitochondrial stromal activation. This review analyzes the radiochemical basis of synovitis imaging, beginning with the radionuclide-dependent behavior of 11C, 68Ga, 64Cu, [Al18F]2+, and 99mTc, and then linking these properties to chelator selection, covalent radiolabeling, labeling conditions, and pharmacokinetics. The review further examines the development of radioligands targeting fibroblast activation protein (FAP), integrin αvβ3, folate receptor beta (β-FR), CXCR4, and the 18 kDa translocator protein (TSPO). It covers FAP-inhibitor scaffolds, RGD-based integrin probes, pteroyl-glutamate folate conjugates, CXCR4 antagonists, and TSPO heteroaromatic ligands. Clinical and translational datasets are discussed in relation to disease-activity evolution, treatment-response monitoring, and differentiation of stromal activation, macrophage infiltration, angiogenesis, and immune-cell recruitment. Finally, the review integrates kinetic modeling and dosimetric translation, emphasizing absorbed-dose estimation as a perspective on therapeutic optimization and safety constraints for emerging β-emitting and α-emitting synovial theranostics, 177Lu and 225Ac. Collectively, these developments define a bench-to-bedside framework for rheumatology precision medicine, in which radiopharmaceutical chemistry, molecular imaging, clinical trial evidence, and patient-specific dosimetry converge to guide diagnosis, therapeutic selection, and future targeted synovial micro-radioresection.