A Novel Radiotracer for NTSR1-Targeted PET Imaging of Tumor: Preclinical and First-in-Human Studies

  • J Med Chem. 2025 Dec 11;68(23):25186-25197. doi: 10.1021/acs.jmedchem.5c02195.
Jiamin Zhu  1  2 ,  Hui Yuan  3 ,  Boyu Tan  1  4  5 ,  Xiufeng Liu  3 ,  Kun Qian  1 ,  Yuanpeng Jiang  1  2 ,  Renda Li  1  6 ,  Wenqing Zhang  1  2 ,  Chunrong Qu  1 ,  Zhen Cheng  1  2  7 ,  Lei Jiang  3
Affiliations
  • 1. State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3. PET Center, Department of Nuclear Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
  • 4. School of Biomedical Engineering, ShanghaiTech University, Shanghai 201210, China.
  • 5. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 6. Institute of Molecular Medicine, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China.
  • 7. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research, Institute for Drug Discovery, Yantai, Shandong 264117, China.
PMID: 41294013 DOI: 10.1021/acs.jmedchem.5c02195
Abstract

Neurotensin Receptor 1 (NTSR1) is overexpressed in various cancers, making it an attractive target for tumor imaging and therapy. However, current NTSR1-targeting peptides derived from neurotensin (NT) analogs face challenges including rapid metabolic clearance and insufficient tumor uptake, limiting their clinical translation. To address this, we developed a novel probe, [68Ga]Ga-DOTA-NT-20.3-IPBA, by conjugating the DOTA-NT-20.3 probe with an albumin-binding moiety (4-(p-iodophenyl)butyric acid [IPBA]). The resulting tracer exhibited enhanced lipophilicity and albumin-binding capacity, while maintaining reasonable in vitro stability, radiochemical yield, and purity (all >95%). In vitro and in vivo evaluations confirmed its high affinity and specificity for NTSR1. Clinical PET/CT imaging demonstrated significant tracer accumulation in lung adenocarcinoma, with a tumor-to-lung ratio of 7.89 ± 0.76 at 60 min postinjection and a favorable biodistribution profile. Collectively, [68Ga]Ga-DOTA-NT-20.3-IPBA shows high potential as a PET tracer for NTSR1-expressing tumors and DOTA-NT-20.3-IPBA may be a promising candidate for future theranostic development.

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