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68Ga-NOTA-m-SNA006: A Next-Generation CD8-Targeting Nanobody Probe for Enhanced Renal and Hepatic Clearance in Noninvasive ImmunoPET Imaging
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  • Tukang Peng,
  • Chao Wang,
  • Jun Wen,
  • Qingyu Zhang,
  • Cheng Wang,
  • Chun Lv,
  • Fuqiang Du,
  • Zhoumi Hu,
  • Tao Xu,
  • Gang Huang,
  • Jianjun Liu,
  • Haitao Zhao
Tukang Peng
Shanghai Jiao Tong University
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Chao Wang
Smart-Nuclide Biotech
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Jun Wen
Shanghai Jiao Tong University
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Qingyu Zhang
Shanghai Normal University
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Cheng Wang
Shanghai Jiao Tong University
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Chun Lv
Shanghai Jiao Tong University
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Fuqiang Du
Shanghai Jiao Tong University
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Zhoumi Hu
Shanghai Jiao Tong University
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Tao Xu
Smart-Nuclide Biotech
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Gang Huang
Shanghai University of Medicine and Health Sciences
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Jianjun Liu
Shanghai Jiao Tong University
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Haitao Zhao
Shanghai Jiao Tong University

Corresponding Author:zhaohaitao@renji.com

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Abstract

Background and purpose The 68Ga-labeled nanobody SNA006 marks a significant advancement in noninvasive ImmunoPET imaging of CD8+ T cells, facilitating real-time tracking of cellular immune responses in cancer, yet its pharmacokinetic properties remain suboptimal. This study aimed to develop a next-generation CD8-targeting immunoPET nanobody probe by incorporating a PEGylated brush border membrane enzyme-cleavable linker to improve pharmacokinetics and to evaluate its characterization in CD8-positive intrapulmonary tumors. Experimental approach A precursor based on SNA006, containing a PEGylated brush border membrane enzyme-cleavable linker, was designed, synthesized, and radiolabeled with gallium-68 to yield 68Ga-NOTA-m-SNA006. The probe was subsequently assessed both in vitro and in vivo. Key results The probe exhibited high radiochemical yield, purity, and favorable stability, and demonstrated binding to the CD8 protein with high affinity. PET/CT imaging and biodistribution studies revealed that 68Ga-NOTA-m-SNA006 exhibited favorable pharmacokinetic properties, including rapid clearance from the kidneys, reduced liver uptake, and sustained retention in the tumor, compared with 68Ga-NODAGA-SNA006. 68Ga-NOTA-m-SNA006 exhibited high uptake in lung lesions during in vivo PET imaging, reflecting CD8 expression in an intrapulmonary tumor model. Conclusion and implication In summary, we present a novel 68Ga-labeled SNA006 radiotracer with an optimized linker moiety, 68Ga-NOTA-m-SNA006, which effectively decreases renal and hepatic uptake while maintaining tumor uptake, thereby enhancing the tumor-to-background ratio. This approach represents a critical advancement in addressing the persistent challenge of radioactivity in the kidneys and liver associated with nanobody-based radiopharmaceuticals.