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

• Published in: Journal of medicinal chemistry 2024-05, Vol.67 (10), p.8460-8472
• Main Authors: Meng, Lingxin, Fang, Jianyang, Zhang, Jingru, Li, Huifeng, Xia, Dongsheng, Zhuang, Rongqiang, Chen, Haojun, Huang, Jinxiong, Li, Yesen, Zhang, Xianzhong, Guo, Zhide
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00772

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 Tc-labeled dimeric HF with high tumor uptake and image contrast. The dimeric HF was synthesized and radiolabeled with Tc in one pot using various coligands (tricine, TPPTS, EDDA, and TPPMS) to yield [ Tc]Tc-TPPTS-HF , [ Tc]Tc-EDDA-HF , and [ Tc]Tc-TPPMS-HF dimers. SPECT imaging results indicated that [ Tc]Tc-TPPTS-HF exhibited higher tumor uptake and tumor-to-normal tissue (T/NT) ratio than [ Tc]Tc-EDDA-HF and [ Tc]Tc-TPPMS-HF . Notably, [ Tc]Tc-TPPTS-HF exhibited remarkable tumor accumulation and retention in HT-1080-FAP and U87-MG tumor-bearing mice, thereby surpassing the monomeric [ Tc]Tc-TPPTS-HF. Moreover, [ Tc]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 Tc-labeled FAP inhibitor dimers for the visualization of multiple tumor types. Among these candidate compounds, [ Tc]Tc-TPPTS-HF showed excellent clinical potential, thereby enriching the SPECT tracer toolbox.