Fibroblast activation protein (FAP) is a potential target for tumor diagnosis and treatment because it is selectively expressed on the cell membrane of cancer-associated fibroblasts in most solid tumor stroma. The aim of this study was to develop a ^99mTc-labeled fibroblast activation protein inhibitor (FAPI) tracer, evaluate its imaging efficacy in nude mice, and further explore its biodistribution in healthy volunteers and uptake in tumor patients. An FAPI-derived ligand (DP-FAPI) containing d-proline was designed and synthesized as a linker, and a stable hydrophilic ^99mTc-labeled complex ([^99mTc]Tc-DP-FAPI) was obtained by kit formulation. In vitro cellular uptake and saturation binding assays were performed in FAP-transfected HT-1080 cells (FAP-HT-1080). The biodistribution was characterized, and micro-single-photon emission computed tomography (SPECT) imaging was performed in BALB/c nude mice bearing U87 MG tumors. Furthermore, a first-in-man application was performed in four healthy volunteers and three patients with gastrointestinal tumors. In vitro, the nanomolar K_d values of [^99mTc]Tc-DP-FAPI indicated that it had significantly high target affinity for FAP. Biodistribution and micro-SPECT imaging studies showed that [^99mTc]Tc-DP-FAPI exhibited high uptake and high tumor-to-nontargeted ratios. The calculated effective dose for [^99mTc]Tc-DP-FAPI was approximately <5 mSv in four healthy volunteers. In three patients with gastrointestinal tumors, [^99mTc]Tc-DP-FAPI quantitative SPECT/CT revealed high and reliable uptake. [^99mTc]Tc-DP-FAPI exhibited high selectivity and affinity for FAP in vitro. The safety and effectiveness of [^99mTc]Tc-DP-FAPI in primary tumor imaging have been confirmed by animal and clinical studies, revealing the potential clinical application value of this tracer.

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