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

Abstract The norepinephrine transporter (NET) represents a validated target for theranostics in neuroendocrine tumors, yet clinical agents such as [123I]/[131I]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 ortho-131I-PhOG was efficiently prepared (RCY 45%, RCP >98%) and exhibited enhanced NET affinity and prolonged intracellular retention compared to [131I]mIBG. In PC-12 xenograft models, ortho-131I-PhOG achieved significantly higher tumor uptake and superior SPECT/CT contrast. At half the dose, ortho-131I-PhOG exerted comparable tumor growth inhibition (TGI = 92.9%) to 10.0 MBq [131I]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 ortho-131I-PhOG as a promising candidate for neuroendocrine tumor theranostics.