Fibroblast Activation Protein-Targeted SPECT Imaging Using ^99mTc: A Comprehensive Review

Fibroblast activation protein (FAP) is a type II transmembrane serine protease that is highly expressed in cancer-associated fibroblasts in the tumor microenvironment of over 90% of epithelial malignancies, and is largely absent in normal tissues. This tumor-selective expression profile positions FAP as an ideal target for molecular imaging and theranostic applications. Despite outstanding clinical results of Positron emission Tomography (PET) based FAP inhibitors (FAPI), their routine use is constrained by high cost, infrastructure demands and the limited availability of radionuclides especially in places where PET camera is not available. Single Photon Emission Computed Tomography (SPECT) imaging based radiotracers labeled with Technetium-99m (^99mTc) have emerged as cost effective, globally accessible alternatives for targeting FAP. This review summarizes recent advancements in the development of ^99mTc-labeled FAPI radiopharmaceuticals, their radiolabeling strategies, and biological evaluation in preclinical and clinical setting. We systematically described ^99mTc coordination strategies for radiolabeling including oxo, nitrido, tricarbonyl, isonitrile and HYNIC-based systems approaches, analyzing their preclinical performance and clinical translation status. Current evidence demonstrates that [^99mTc]Tc-FAPI radiotracers show high tumor uptake, good pharmacokinetic properties and excellent imaging contrast which has led to their potential in clinical translation in imaging FAP.