Synthesis and Evaluation of Radiogallium-Labeled Peptide Probes for In Vivo Imaging of Legumain Activity

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Abstract
Legumain (LGMN), a lysosomal cysteine protease, is crucial for tumor progression, invasion, and metastasis, making it a promising target for cancer imaging and therapy. This study developed novel 67Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-conjugated LGMN-cleavable peptide probes ([67Ga]Ga-NOTA-LCPs) composed of polyarginine and polyglutamic acid sequences linked by LGMN-cleavable sites for nuclear medicine imaging of LGMN activity. The probes were synthesized via fluorenylmethoxycarbonyl solid-phase peptide synthesis and radiolabeled in high radiochemical yields. In vitro assays with HCT116 cells showed significantly higher uptake of [67Ga]Ga-NOTA-LCPs compared to non-cleavable controls, confirming efficient cleavage and cellular uptake. In vivo studies in tumor-bearing mice revealed rapid renal clearance, low non-specific binding, and favorable tumor-to-blood ratios, particularly for [67Ga]Ga-NOTA-LCP-1. These results demonstrate the potential of [67Ga]Ga-NOTA-LCPs as effective LGMN-responsive imaging agents, with further optimization needed to improve tumor specificity and reduce off-target accumulation.
Funding Information
  • Grant-in-Aid for Scientific Research (22H03015)
  • Grant-in-Aid for Scientific Research (15K09895, 18K07756)
  • Japan Science and Technology Agency (JPMJFR200V)
  • Takeda Science Foundation
  • Kobayashi Foundation for Cancer Research
  • Terumo Life Science Foundation
  • NOVARTIS Foundation (Japan) for the Promotion of Science
  • Shibuya Science Culture and Sports Foundation
  • Hitachi Global Foundation
  • Shimadzu Science Foundation
  • Hokkoku Cancer Foundation
  • Kieiotoyo Foundation
  • Nakatomi Foundation
  • Kanazawa University SAKIGAKE Project (2022, 2024)

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