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Structural Optimization of NET-Targeted Agents: -Radioiodinated Phenoxyalkylguanidine Achieves Enhanced Tumor Retention and Radiotherapeutic Efficacy.

2026-05-29, Journal of Medicinal Chemistry (10.1021/acs.jmedchem.6c00536) (online)
Ning Liu, Feize Li, Wei Chen, Xijian Chen, Lili Pan, Yueqi Wang, Yang Xie, Yarong Cao, Mingxing Hu, Jinsong Zhang, and Ning Luo (?)
The norepinephrine transporter (NET) represents a validated target for theranostics in neuroendocrine tumors, yet clinical agents such as [I]/[I]mIBG exhibit suboptimal tumor retention, deiodination, and dose-limiting toxicity. To address these limitations, we designed and synthesized a series of radioiodinated phenoxyalkylguanidine (PhOG) derivatives by replacing the conventional benzyl moiety with a phenoxyalkyl spacer to increase tumor uptake and enhance metabolic stability. The -I-PhOG was efficiently prepared (RCY 45%, RCP >98%) and exhibited enhanced NET affinity and prolonged intracellular retention compared to [I]mIBG. In PC-12 xenograft models, -I-PhOG achieved significantly higher tumor uptake and superior SPECT/CT contrast. At half the dose, -I-PhOG exerted comparable tumor growth inhibition (TGI = 92.9%) to 10.0 MBq [I]mIBG, with prolonged survival and no obvious toxicity. These results underscore that the strategic incorporation of a phenoxyalkyl linker improves the pharmacokinetic and therapeutic profiles of NET-targeted radiopharmaceuticals, positioning -I-PhOG as a promising candidate for neuroendocrine tumor theranostics.
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