2. Academic Validation
  3. Rational modifications on N-(4-quinolinoyl)-Gly-2-cyanopyrrolidine to develop fibroblast activation protein-targeted radioligands with improved affinity and tumor uptake

Rational modifications on N-(4-quinolinoyl)-Gly-2-cyanopyrrolidine to develop fibroblast activation protein-targeted radioligands with improved affinity and tumor uptake

  • Eur J Med Chem. 2025 Jan 5:281:117011. doi: 10.1016/j.ejmech.2024.117011.
Xinyan Qiu 1,  Qianqian Gan 2,  Tianxiong Ji 3,  Hongchuang Xu 4,  Kai Cui 4,  Long Yi 5,  Xing Yang 6,  Min-Fu Yang 7
Affiliations

Affiliations

  • 1 Beijing University of Chemical Technology, Beijing, 100029, China; SINOPEC (Beijing) Research Institute of Chemical Industry Co., Ltd., Beijing, 100013, China.
  • 2 Department of Nuclear Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
  • 3 Department of Nuclear Medicine, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, 030001, China; Shanxi Key Laboratory of Molecular Imaging and Collaborative Innovation Center for Molecular Imaging of Precision Medicine, Shanxi Medical University, Taiyuan, 030001, China.
  • 4 Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China.
  • 5 Beijing University of Chemical Technology, Beijing, 100029, China. Electronic address: yilong@mail.buct.edu.cn.
  • 6 Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China; Department of Central Laboratory, Peking University First Hospital, Beijing, 100034, China; Yunnan Baiyao Group, Kunming, 650000, China. Electronic address: yangxing2017@bjmu.edu.cn.
  • 7 Department of Nuclear Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China. Electronic address: minfuyang@126.com.
PMID: 39488967 DOI: 10.1016/j.ejmech.2024.117011
Abstract

Fibroblast activation protein (FAP) has been an attractive target for Cancer imaging and therapy. Radiolabeled FAP-targeting ligands have shown promising results for clinical applications. However, further improvements are ongoing in pursuit of increasing tumor uptake, prolonging tumor residence, and maintenance good tumor-to-background contrast for extensive theranostic application. Achieving a higher affinity of the precursor is one of the ways in research. In this study, we designed a series of FAP inhibitors based on N-(4-quinolinoyl)-Gly-2-cyanopyrrolidine and found compound QI-18 with an IC50 value of 0.50 nM, which is a 6.5-fold increase in potency over that of UAMC-1110 (IC50 of 3.25 nM). QI-18 was then functionalized with a DOTA chelator to obtain the ligand CY03 for further radiolabeling with 68Ga to obtain the radiotracer [68Ga]Ga-CY03. In BALB/c nude mice bearing U87MG tumor models, [68Ga]Ga-CY03 exhibited a high and specific uptake (10.30 ± 0.63 % ID/g at 1 h post-injection and 9.28 ± 1.60 % ID/g at 2 h post-injection), which represented 3.2- and 4.1-fold increases over those for [68Ga]Ga-FAPI-04 (3.24 ± 0.53 % ID/g and 2.25 ± 0.33 % ID/g, respectively). [68Ga]Ga-CY03 also showed higher tumor-to-blood and tumor-to-kidney ratios (7.62 ± 0.44 and 2.59 ± 0.27, respectively) than [68Ga]Ga-FAPI-04 (2.38 ± 0.47 and 0.98 ± 0.19, respectively). The results indicate that [68Ga]Ga-CY03 is a promising imaging agent to target FAP.

Keywords

Cancer imaging; Fibroblast activation protein inhibitor; PET; Tumor uptake.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-159934
    Fibroblast Activation Protein Inhibitor
    FAP