2. Academic Validation
  3. Structure-guided design and clinical evaluation of 68Ga-GP01 for FAP-targeted PET imaging in solid tumors

Structure-guided design and clinical evaluation of 68Ga-GP01 for FAP-targeted PET imaging in solid tumors

  • J Control Release. 2026 Jan 10:389:114475. doi: 10.1016/j.jconrel.2025.114475.
Xingyu Mu 1,  Zihao Chen 2,  Hoi Yee Chow 3,  Jingze Li 1,  Jian Li 1,  Lei Zhang 1,  Weixia Chong 1,  Yufeng Mo 1,  Kam Pui Tam 3,  Weikun Tang 4,  Wentao Huang 4,  Shuheng Liang 4,  Yaxin Shi 4,  Mutian Cui 4,  Xin Zhang 5,  Ganghua Tang 6,  Xuechen Li 7,  Wei Fu 8
Affiliations

Affiliations

  • 1 Department of Nuclear Medicine, The First Affiliated Hospital, Guilin Medical University, Guilin 541001, China.
  • 2 Key Laboratory Project of Guangdong Provincial Department of Education for Ordinary Universities and GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 3 Serilink Biotechnology Company Limited, Hong Kong 999077, China.
  • 4 Grand Pharma (China) Company Limited, Wuhan 430000, China.
  • 5 Department of Radiation Oncology, The First Affiliated Hospital, Guilin Medical University, Guilin 541001, China. Electronic address: zhangxin1262008@126.com.
  • 6 Key Laboratory Project of Guangdong Provincial Department of Education for Ordinary Universities and GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: gtang0224@smu.edu.cn.
  • 7 Department of Chemistry, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong 999077, China. Electronic address: xuechenl@hku.hk.
  • 8 Department of Nuclear Medicine, The First Affiliated Hospital, Guilin Medical University, Guilin 541001, China. Electronic address: fuwei19700513@163.com.
PMID: 41325906 DOI: 10.1016/j.jconrel.2025.114475
Abstract

Fibroblast activation protein (FAP)-targeted radioligands have shown superior performance in detecting FAP-expressing cancers. However, the quinoline-based agent 68Ga-FAPI-46 exhibits only moderate in vivo stability and suboptimal pharmacokinetics. To overcome these limitations, a FAP Inhibitor, GP01 was designed by introducing N-methyl-benzenesulfonic acid side chain on FAPI-46 with enhanced binding affinity and improved in vivo stability. 68Ga-GP01 demonstrated high radiochemical purity, favorable binding energy, and excellent in vitro stability. It specifically bound to FAP on A549-hFAP and U87MG cells, exhibiting greater uptake, enhanced internalization, and slower efflux compared to 68Ga-FAPI-46. In vivo PET/CT imaging revealed that 68Ga-GP01 accumulated specifically in FAP-positive tumor models, with improved pharmacokinetic behavior and a higher tumor-to-background ratio than 68Ga-FAPI-46. Tumor uptake correlated significantly with both ex vivo biodistribution and immunohistochemical FAP expression. Clinical evaluation in 35 patients with solid tumors revealed that 68Ga-GP01 has optimal pharmacokinetics, persistent target engagement and promising lesion detection, delivering a low effective dose with no adverse events within 6 h post-injection. Furthermore, in a direct comparison with 18F-FDG, 68Ga-GP01 detected more lesions and achieved higher uptake and tumor-to-background ratios. These data support 68Ga-GP01 as a clinically translatable FAP-targeted PET tracer and motivate prospective trials in indications where stromal imaging augments or surpasses metabolic imaging.

Keywords

(68)Ga-GP01; Fibroblast activation protein; PET/CT imaging; Radiotracer design; Solid tumors.

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