EANM innovation最新文献

{"title":"SSTR2 receptor states and cellular metabolism modulate ¹⁷⁷Lu-DOTATATE binding affinity.","authors":"Sara Lundsten Salomonsson, Pleun A M Engbers, Julie Nonnekens, Sina Bondza","doi":"10.1016/j.eanmi.2026.100288","DOIUrl":"https://doi.org/10.1016/j.eanmi.2026.100288","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are the target for approximately 36% of approved drugs and control many cell signaling pathways. Among these is the somatostatin receptor 2 (SSTR2), which can be targeted by the radiolabeled somatostatin analog [¹⁷⁷Lu]Lu-DOTA-Tyr³-octreotate (¹⁷⁷Lu-DOTATATE) for treatment of neuroendocrine cancers. Here, we provide a detailed kinetic characterization of the uptake and retention dynamics for ¹⁷⁷Lu-DOTATATE binding to SSTR2 on live tumor cells to gain a deeper understanding on how observed binding affinities relate to receptor biology and subsequent treatment outcome. Real-time cell binding assays have revealed two main interaction populations distinguished primarily by their retention times. High-affinity binding in the sub-nanomolar range was associated with ¹⁷⁷Lu-DOTATATE interacting with G protein-coupled receptors, whereas low-affinity binding in the nanomolar range corresponded to interactions with uncoupled receptors. Cells fixed prior to ligand exposure also exhibited high-affinity binding, although to a lesser degree, implying the presence of pre-coupled SSTR2. Cellular retention decreased with ligand exposure, suggesting a shift in receptor coupling state after prolonged stimulation. Intracellular accumulation upon ligand stimulation was confirmed for both ¹⁷⁷Lu-DOTATATE and SSTR2. Unlabeled DOTATATE was able to induce excretion of internalized ¹⁷⁷Lu-DOTATATE, revealing a highly dynamic interaction with constant turnover of ligands. This study highlights the dynamic nature of agonists binding to GPCRs in a live cell environment. By employing cell-based real-time binding assays, we were able de-convolute the contribution of distinct receptor states to ¹⁷⁷Lu-DOTATATE affinity and retention and study the impact of internalization and recycling dynamics. Improved understanding of ligand/drug-GPCR interactions and how these are impacted by the cellular environment and metabolism can be used to optimize existing and new therapeutic approaches.</p>","PeriodicalId":524229,"journal":{"name":"EANM innovation","volume":"4 ","pages":"None"},"PeriodicalIF":0.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149123877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}