[¹⁷⁷Lu]Lu-XYIMSR-01: A Novel CAIX-Targeted Radiotherapeutic for Enhanced Treatment of Malignant Glioma

Malignant glioma highly expresses carbonic anhydrase IX (CAIX). This study aimed to develop [¹⁷⁷Lu]Lu-XYIMSR-01, a small-molecule therapeutic agent CAIX, to assess its potential for treating malignant glioma. [¹⁷⁷Lu]Lu-XYIMSR-01 was synthesized by radiolabeling DOTA-XYIMSR-01 with ¹⁷⁷Lu. In vitro assays were conducted to evaluate the affinity for U87MG tumor cells. The probe was injected via the tail vein into subcutaneous and orthotopic U87MG models for micro-SPECT/CT imaging. The survival rates of tumor-bearing mice were assessed after [¹⁷⁷Lu]Lu-XYIMSR-01 injection by intratumoral in orthotopic models, including untreated controls and those treated with Temozolomide or combination therapy. After purification, the radiochemical yield of [¹⁷⁷Lu]Lu-XYIMSR-01 was 86.47 ± 2.42%, with a radiochemical purity (RCP) of 99%. Its cell uptake in U87MG cells was 3.70 ± 0.57 ‰ AD/10⁵ cells, significantly higher than that in HCT116 cells (0.68 ± 0.16 ‰ AD/10⁵ cells, <i>P</i> = 0.001). In the biodistribution study, [¹⁷⁷Lu]Lu-XYIMSR-01 uptake in U87MG tumors was 6.19 ± 1.37%ID/g, with a tumor/muscle ratio of 20.14 ± 3.24. In the orthotopic glioma model, local injection combined with Temozolomide significantly improved survival and inhibited tumor growth. The results indicate that [¹⁷⁷Lu]Lu-XYIMSR-01 is a promising therapeutic molecular probe for targeting CAIX, and its combination with Temozolomide significantly enhances treatment outcomes for malignant glioma.