Design, Synthesis, and Evaluation of [68Ga/177Lu]-Labeled TSPO-Targeting Radioligands for PET/CT Diagnosis and Radionuclide Therapy of Brain Tumor.

The translocator protein (TSPO) has gained increasing attention in the diagnosis and treatment of brain cancers. Current TSPO-targeting radiotracers, predominantly labeled with 11C and 18F, limit the incorporation of emerging radionuclides into theranostic applications. In this study, we designed and synthesized four DOTA-conjugated TSPO-targeting precursors featuring various polyethylene glycol (PEG) linkers, which enabled straightforward and efficient labeling with 68Ga or 177Lu. In vitro and in vivo evaluations demonstrated that compared with [18F]FDG, all four 68Ga-labeled radioligands exhibited specific accumulation in glioblastoma in an orthotopic U87MG tumor-bearing mouse model. Among them, [68Ga]TSPO-1 displayed more favorable physicochemical properties, binding affinity, and, notably, the highest uptake in U87MG tumor tissues. Furthermore, [177Lu]TSPO-1 significantly inhibited U87MG tumor growth in the mouse model with satisfactory biosafety, implying its potent therapeutic potential for glioblastomas. In summary, this study develops DOTA-conjugated radioligands targeting TSPO and highlights the promise of [68Ga/177Lu]TSPO-1 for radiotheranostic applications in brain oncology.