Rational Design and Comparison of Novel 99mTc-Labeled FAPI Dimers for Visualization of Multiple Tumor Types

Recognizing the significance of SPECT in nuclear medicine and the pivotal role of fibroblast activation protein (FAP) in cancer diagnosis and therapy, this study focuses on the development of 99mTc-labeled dimeric HF2 with high tumor uptake and image contrast. The dimeric HF2 was synthesized and radiolabeled with 99mTc in one pot using various coligands (tricine, TPPTS, EDDA, and TPPMS) to yield [99mTc]Tc-TPPTS-HF2, [99mTc]Tc-EDDA-HF2, and [99mTc]Tc-TPPMS-HF2 dimers. SPECT imaging results indicated that [99mTc]Tc-TPPTS-HF2 exhibited higher tumor uptake and tumor-to-normal tissue (T/NT) ratio than [99mTc]Tc-EDDA-HF2 and [99mTc]Tc-TPPMS-HF2. Notably, [99mTc]Tc-TPPTS-HF2 exhibited remarkable tumor accumulation and retention in HT-1080-FAP and U87-MG tumor-bearing mice, thereby surpassing the monomeric [99mTc]Tc-TPPTS-HF. Moreover, [99mTc]Tc-TPPTS-HF2 achieved acceptable T/NT ratios in the hepatocellular carcinoma patient-derived xenograft (HCC-PDX) model, which provided identifiable contrast and imaging quality. In conclusion, this study presents proof-of-concept research on 99mTc-labeled FAP inhibitor dimers for the visualization of multiple tumor types. Among these candidate compounds, [99mTc]Tc-TPPTS-HF2 showed excellent clinical potential, thereby enriching the SPECT tracer toolbox.

鉴于单光子发射计算机断层成像术（SPECT）在核医学领域的重要价值，以及成纤维细胞激活蛋白（FAP）在癌症诊疗中的关键作用，本研究旨在开发兼具高肿瘤摄取能力与优异成像对比度的锝-99m标记二聚体HF2。本研究通过一锅法，使用多种辅配体（三羟甲基甘氨酸（tricine）、三(间-磺酸钠苯基)膦（TPPTS）、乙二胺二乙酸（EDDA）与三苯基单膦单磺酸钠（TPPMS））完成二聚体HF2的合成与锝-99m放射性标记，成功获得[99mTc]Tc-TPPTS-HF2、[99mTc]Tc-EDDA-HF2与[99mTc]Tc-TPPMS-HF2三种二聚体产物。单光子发射计算机断层成像术成像结果表明，[99mTc]Tc-TPPTS-HF2的肿瘤摄取水平与肿瘤/正常组织（T/NT）比值均优于[99mTc]Tc-EDDA-HF2与[99mTc]Tc-TPPMS-HF2。值得注意的是，[99mTc]Tc-TPPTS-HF2在转染成纤维细胞激活蛋白的HT-1080细胞荷瘤小鼠与U87-MG胶质瘤荷瘤小鼠中展现出显著的肿瘤聚集与滞留能力，其性能优于单体形式的[99mTc]Tc-TPPTS-HF。此外，[99mTc]Tc-TPPTS-HF2在肝细胞癌患者来源异种移植（HCC-PDX）模型中获得了可接受的肿瘤/正常组织比值，成像对比度与图像质量均清晰可辨。综上，本研究完成了锝-99m标记的成纤维细胞激活蛋白抑制剂二聚体的概念验证研究，实现了多种肿瘤类型的可视化成像。在本次研究的候选化合物中，[99mTc]Tc-TPPTS-HF2展现出优异的临床转化潜力，为单光子发射计算机断层成像术显像剂工具箱增添了新的选择。