1. Academic Validation
  2. Development of Fibroblast Activation Protein-Targeted Radiotracers with Improved Tumor Retention

Development of Fibroblast Activation Protein-Targeted Radiotracers with Improved Tumor Retention

  • J Nucl Med. 2019 Oct;60(10):1421-1429. doi: 10.2967/jnumed.118.224469.
Anastasia Loktev 1 2 Thomas Lindner 1 Eva-Maria Burger 1 Annette Altmann 1 2 Frederik Giesel 1 Clemens Kratochwil 1 Jürgen Debus 3 4 Frederik Marmé 5 Dirk Jäger 6 Walter Mier 1 Uwe Haberkorn 7 2 8
Affiliations

Affiliations

  • 1 Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany.
  • 2 Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany.
  • 3 Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany.
  • 4 Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center, Heidelberg, Germany.
  • 5 Department of Gynecologic Oncology, National Center for Tumor Diseases and Department of Obstetrics and Gynecology, University Women's Clinic, University Hospital Heidelberg, Heidelberg, Germany.
  • 6 Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany; and.
  • 7 Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany uwe.haberkorn@med.uni.
  • 8 Translational Lung Research Center Heidelberg, German Center for Lung Research, Heidelberg, Germany.
Abstract

Cancer-associated fibroblasts constitute a vital subpopulation of the tumor stroma and are present in more than 90% of epithelial carcinomas. The overexpression of the serine protease fibroblast activation protein (FAP) allows a selective targeting of a variety of tumors by inhibitor-based radiopharmaceuticals (FAPIs). Of these compounds, FAPI-04 has been recently introduced as a theranostic radiotracer and demonstrated high uptake into different FAP-positive tumors in Cancer patients. To enable the delivery of higher doses, thereby improving the outcome of a therapeutic application, several FAPI variants were designed to further increase tumor uptake and retention of these tracers. Methods: Novel quinoline-based radiotracers were synthesized by organic chemistry and evaluated in radioligand binding assays using FAP-expressing HT-1080 cells. Depending on their in vitro performance, small-animal PET imaging and biodistribution studies were performed on HT-1080-FAP tumor-bearing mice. The most promising compounds were used for clinical PET imaging in 8 Cancer patients. Results: Compared with FAPI-04, 11 of 15 FAPI derivatives showed improved FAP binding in vitro. Of these, 7 compounds demonstrated increased tumor uptake in tumor-bearing mice. Moreover, tumor-to-normal-organ ratios were improved for most of the compounds, resulting in images with higher contrast. Notably two of the radiotracers, FAPI-21 and -46, displayed substantially improved ratios of tumor to blood, liver, muscle, and intestinal uptake. A first diagnostic application in Cancer patients revealed high intratumoral uptake of both radiotracers already 10 min after administration but a higher uptake in oral mucosa, salivary glands, and thyroid for FAPI-21. Conclusion: Chemical modification of the FAPI framework enabled enhanced FAP binding and improved pharmacokinetics in most of the derivatives, resulting in high-contrast images. Moreover, higher doses of radioactivity can be delivered while minimizing damage to healthy tissue, which may improve therapeutic outcome.

Keywords

FAP inhibitor; PET/CT; fibroblast activation protein; theranostics; tracer development.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-137331
    98.57%, 放射性示踪剂
    FAP
  • HY-128643
    98.42%, FAP抑制剂
    FAP