Rational Design and Comparison of Novel 99m Tc-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 ^99m Tc-labeled dimeric HF ₂ with high tumor uptake and image contrast. The dimeric HF ₂ was synthesized and radiolabeled with ^99m Tc in one pot using various coligands (tricine, TPPTS, EDDA, and TPPMS) to yield [ ^99m Tc]Tc-TPPTS-HF ₂ , [ ^99m Tc]Tc-EDDA-HF ₂ , and [ ^99m Tc]Tc-TPPMS-HF ₂ dimers. SPECT imaging results indicated that [ ^99m Tc]Tc-TPPTS-HF ₂ exhibited higher tumor uptake and tumor-to-normal tissue (T/NT) ratio than [ ^99m Tc]Tc-EDDA-HF ₂ and [ ^99m Tc]Tc-TPPMS-HF ₂ . Notably, [ ^99m Tc]Tc-TPPTS-HF ₂ exhibited remarkable tumor accumulation and retention in HT-1080-FAP and U87-MG tumor-bearing mice, thereby surpassing the monomeric [ ^99m Tc]Tc-TPPTS-HF. Moreover, [ ^99m 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 ^99m Tc-labeled FAP inhibitor dimers for the visualization of multiple tumor types. Among these candidate compounds, [ ^99m Tc]Tc-TPPTS-HF ₂ showed excellent clinical potential, thereby enriching the SPECT tracer toolbox.