Development of [68Ga]Ga/[177Lu]Lu-DOTA-NI-FAPI-04 Containing a Nitroimidazole Moiety as New FAPI Radiotracers with Improved Tumor Uptake and Retention

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL
Yang Luo, Wenbin Jin, Jie Zang, Guochang Wang, Lin Zhu, Hank F. Kung
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引用次数: 0

Abstract

Fibroblast activation protein (FAP), which is overexpressed in cancer-associated fibroblasts (CAFs), represents a promising target for cancer diagnosis and therapy. Hypoxia is a common feature of solid tumors. A bivalent agent, DOTA-NI-FAPI-04 (1), was developed by incorporating hypoxia-sensitive nitroimidazole (NI) into the FAP-targeting agent FAPI-04. Compound 1 exhibited a strong FAP binding affinity with an IC50 of 7.44 nM. Radiolabeled [68Ga]Ga-1 and [177Lu]Lu-1 demonstrated enhanced in vitro cell uptake. In vivo positron emission tomography/computed tomography (PET/CT) imaging showed that [68Ga]Ga-1 displayed significantly higher specific uptake and retention in U87MG tumor-bearing mice compared to [68Ga]Ga-FAPI-04 (SUVavg: 7.87 vs 1.99% ID/mL at 120 min). Biodistribution studies confirmed superior tumor uptake of [68Ga]Ga-1 (48.15 vs 5.72% ID/g at 120 min). Similarly, [177Lu]Lu-1 exhibited higher tumor uptake than [177Lu]Lu-FAPI-04 (50.75 vs 20.48% ID/g at 120 min). These preliminary results suggest that a nitroimidazole-containing bivalent-targeting agent, [68Ga]Ga/[177Lu]Lu-1, is a promising candidate for tumor theranostics.

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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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