{
  "abstract": "Background Colorectal cancer (CRC) accounts for approximately 10% of global cancer incidence and remains a leading cause of cancer-related mortality. FAP-targeted small-molecule inhibitor–based PET/CT has demonstrated improved sensitivity and accuracy over [ 18F]FDG for CRC imaging, particularly in detecting peritoneal metastases. Compared with small molecules, peptide-based ligands exhibit prolonged tumor retention and more favorable pharmacokinetics, supporting their potential in theranostic applications; however, studies in this area remain limited. Here, we report the development of chemically evolved FAP-targeted cyclic peptide tracers with enhanced tumor uptake and retention for clinical CRC imaging.Methods Peptide precursors were synthesized via Fmoc-based solid-phase chemistry, characterized by LC–MS and HPLC, and radiolabeled with 68Ga (RCP >98%). Binding affinity and cellular uptake were assessed in PC12-FAP cells. In vivo PET/CT imaging, biodistribution, and dosimetry were evaluated in PC12-FAP xenograft models, followed by a first-in-human study in CRC patients with primary, postoperative, or post-therapy lesions.Results A library of 24 FAP2286-derived peptides was generated through site-specific fluorination, PEGylation, and N-terminal modification. Among the precursors [ 68Ga]Ga-HKF-020 demonstrated markedly improved binding affinity, higher tumor uptake, and faster clearance from non-target tissues compared with [68Ga]Ga-FAP2286 (IDDF2026-ABS-0404 Figure 1. Cell evaluation and micropetct imaging in PC12-FAP-tumor-bearing mice). Clinically, eight CRC patients with primary, postoperative, or post-therapy lesions were enrolled. In head-to-head comparisons, [68Ga]Ga-HKF-020 achieved higher SUVmax in primary CRC lesions (11.1 vs 5.0) and pelvic nodules (8.3 vs 3.7) (IDDF2026-ABS-0404 Figure 2. First in human study of 68GAGA-HFK-020). Importantly, it enabled clear visualization of postoperative and treated lesions despite relatively low uptake, with superior detection of peritoneal metastases (yellow arrows), which are often underestimated by [18F]FDG imaging (IDDF2026-ABS-0404 Figure 3. 68GAGA-HFK-020 PETCT imaging in CRC patients with primary postoperative or post-therapy lesions).Conclusions This study provides compelling evidence that site-specific fluorination effectively optimized FAP-targeted radioligands. More importantly, [ 68Ga]Ga-HKF-020 shows strong potential for CRC imaging, particularly in detecting peritoneal disease. Collectively, these findings demonstrated [68Ga]Ga-HKF-020 as a valuable diagnostic tool for CRC, supporting its clinical translation for accurate lesion delineation and individualized therapeutic decision-making. Ongoing studies will include head-to-head comparisons with [18F]FDG and 177Lu-labeling to further explore its value in CRC theranostics.Abstract IDDF2026-ABS-0404 Figure 1Abstract IDDF2026-ABS-0404 Figure 2Abstract IDDF2026-ABS-0404 Figure 3",
  "authors": [
    {
      "affiliations": [
        "Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Beijing, China"
      ],
      "name": "Xin Gao"
    },
    {
      "affiliations": [
        "Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Beijing, China"
      ],
      "name": "Linger Li"
    },
    {
      "affiliations": [
        "Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Beijing, China"
      ],
      "name": "Siqi Zhang"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Jinan University, Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine, & Key Laboratory of Basic and Translational Research on Radiopharmaceuticals, China"
      ],
      "name": "Lu Wang"
    },
    {
      "affiliations": [
        "Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Beijing, China"
      ],
      "name": "Rui Wang"
    },
    {
      "affiliations": [
        "Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Beijing, China"
      ],
      "name": "Kuan Hu"
    }
  ],
  "title": "IDDF2026-ABS-0404 First-in-human study of a novel fluorinated fap-targeted cyclic peptide radiotracer for enhanced pet imaging of colorectal cancer",
  "uid": "b6e8ced6-efcc-50f1-8be9-de90562b1796"
}