Nitroimidazole-Containing [ <sup>68</sup> Ga]Ga-IPM-N001 as a New CAIX-Targeting Radionuclide Tracer
Carbonic anhydrase IX (CAIX), which is overexpressed in tumor cells under hypoxic stress, is a promising target for cancer diagnosis and therapy. To enhance tumor uptake and pharmacokinetics, we designed a series of new bivalent CAIX-targeting probes by integrating a hypoxia-sensitive 2-nitroimidazole moiety into the <b>DPI-4452</b> scaffold. Among these, the new agent <b>[</b><sup><b>68</b></sup><b>Ga]Ga-IPM-N001</b> demonstrated superior higher tumor uptake and significantly improved tumor-to-background ratios (<i>T</i>/<i>K</i> and <i>T</i>/<i>L</i> > 5.0) in the PET/CT imaging studies using OS-RC-2 tumor-bearing mice. This probe also exhibited rapid clearance from the gallbladder, intestines, and kidneys while maintaining strong and prolonged tumor retention, thereby limiting potential systemic toxicity in the normal tissues. Surface plasmon resonance analysis further demonstrated that the precursor <b>IPM-N001</b> possesses a comparable or improved CAIX-binding affinity relative to <b>DPI-4452</b>. These findings indicate that this nitroimidazole-containing bivalently targeted agent holds promise as a candidate for the theranostics of clear cell renal cell carcinoma.
Authors
- Peng Teng (ORCID: https://orcid.org/0000-0001-7517-8442)
- Ruhong Zhou
- Jiang‐Jiang Tang (ORCID: https://orcid.org/0000-0003-2598-3456)
- Yichen Xu (ORCID: https://orcid.org/0009-0004-8423-4150)
- Guanqiao Zhang (ORCID: https://orcid.org/0000-0001-9274-9358)
- Shengping Zhang (ORCID: https://orcid.org/0000-0001-5200-3420)
- Haitao Zhang (ORCID: https://orcid.org/0000-0002-1639-4089)
- Lu Wan (ORCID: https://orcid.org/0000-0001-8939-3004)
- Bo Wang (ORCID: https://orcid.org/0000-0002-7547-0088)
- Yaqi Fu
- Kang Chen (ORCID: https://orcid.org/0000-0002-4837-9844)
- Sixuan Cheng
- Peichen Pan
- Xiaowu Dong
- Dawei Jiang
- Xiaoke Niu
Institutions
- Nanjing University of Chinese Medicine (CN)
- Target (United States) (US)
- Neuropsychiatric Research Institute (US)
- Wuhan Institute of Bioengineering (CN)
- Quantitative BioSciences (US)
- Jinhua Academy of Agricultural Sciences (CN)
- Zhejiang Lab (CN)
- Drug Discovery Laboratory (Norway) (NO)
- Kindeva Drug Delivery (United States) (US)
- Huazhong University of Science and Technology Hospital (CN)
- Hangzhou Medical College (CN)
- Huazhong University of Science and Technology (CN)
- Zhejiang University (CN)
- Columbia University (US)
- Northwest A&F University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-03-05
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00481
- Primary Topic
- Enzyme function and inhibition
- Type
- article
- Field-Weighted Citation Impact
- 0.00