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内容記述 |
Aim/Introduction: Metabotropic glutamate receptor 1 (mGluR1), an oncoprotein involved in glutamine metabolism and frequently overexpressed in a wide range of cancers, including melanoma, represents a promising target for pan-cancer management (1-2). Here, we developed a novel pair of mGluR1-targeted radiopharmaceuticals that combines positron emission tomography (PET) imaging and targeted alpha(α) therapy (TAT) for cancer diagnosis and therapy.Methods: Two small-molecule radiopharmaceuticals were synthesized by labeling the same small-molecule compound with either a diagnostic isotope 11C or an α-emitting therapeutic isotope 211At: 3-iodo-N-[4-[6-(methylamino) pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-[11C]methylbenzamide([11C]IMTM) for PET imaging, and 3-[211At]-astato-N-[4-[6-(methylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([211At]AMTM) for TAT. Their diagnostic and therapeutic effects were assessed in vitro and in vivo using mGluR1-expressing B16F10 melanoma cells and corresponding tumor-bearing mouse models.Results: Both [11C]IMTM and [211At]AMTM showed high binding affinity and specificity for mGluR1 in B16F10 cells in vitro. PET imaging with [11C]IMTM clearly visualized subcutaneous and metastatic tumors in B16F10 melanoma models. [211At]AMTM anchored to mGluR1, downregulated this oncoprotein expression, and was subsequently internalized to trigger cancer cell senescence via the p21/caveolin-1 pathway. In vivo, a single dose (2.96 MBq) of [²¹¹At] AMTM significantly inhibited tumor growth and doubled survival in both subcutaneous and metastatic melanoma models. No significant body weight loss or adverse effects on liver or kidney function were observed in treated mice during the study period.Conclusion: The radiopharmaceutical pair [11C]IMTM and [211At]AMTM shows strong precise as mGluR1-targeted radiopharmaceuticals for radiotheranostics. They offer a precise and effective option for diagnosing and treating mGluR1-expressing cancers, such as melanoma, and hold considerable potential for clinical translation. |
