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Emerging evidence suggests that <jats:sup>212<\/jats:sup>Pb-labeled peptide-based radiopharmaceuticals targeting somatostatin receptor subtype 2 (SSTR2) may provide improved effectiveness compared to beta-particle-based therapies for neuroendocrine tumors (NETs). This study aims to improve the performance of SSTR2-targeted radionuclide imaging and therapy through structural modifications to Tyr<jats:sup>3<\/jats:sup>-octreotide (TOC)-based radiopharmaceuticals.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>New SSTR2-targeted peptides were designed and synthesized with the goal of optimizing the incorporation of Pb isotopes through the use of a modified cyclization technique; the introduction of a Pb-specific chelator (PSC); and the insertion of polyethylene glycol (PEG) linkers. The binding affinity of the peptides and the cellular uptake of <jats:sup>203<\/jats:sup>Pb-labeled peptides were evaluated using pancreatic AR42J (SSTR2+) tumor cells and the biodistribution and imaging of the <jats:sup>203<\/jats:sup>Pb-labeled peptides were assessed in an AR42J tumor xenograft mouse model. A lead peptide was identified (i.e., PSC-PEG<jats:sub>2<\/jats:sub>-TOC), which was then further evaluated for efficacy in <jats:sup>212<\/jats:sup>Pb therapy studies.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The lead radiopeptide drug conjugate (RPDC) \u2014 [<jats:sup>203<\/jats:sup>Pb]Pb-PSC-PEG<jats:sub>2<\/jats:sub>-TOC \u2014 significantly improved the tumor-targeting properties, including receptor binding and tumor accumulation and retention as compared to [<jats:sup>203<\/jats:sup>Pb]Pb-DOTA<jats:sup>0<\/jats:sup>-Tyr<jats:sup>3<\/jats:sup>-octreotide (DOTATOC). Additionally, the modified RPDC exhibited faster renal clearance than the DOTATOC counterpart. These advantageous characteristics of [<jats:sup>212<\/jats:sup>Pb]Pb-PSC-PEG<jats:sub>2<\/jats:sub>-TOC resulted in a dose-dependent therapeutic effect with minimal signs of toxicity in the AR42J xenograft model. Fractionated administrations of 3.7 MBq [<jats:sup>212<\/jats:sup>Pb]Pb-PSC-PEG<jats:sub>2<\/jats:sub>-TOC over three doses further improved anti-tumor effectiveness, resulting in 80% survival (70% complete response) over 120 days in the mouse model.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Structural modifications to chelator and linker compositions improved tumor targeting and pharmacokinetics (PK) of <jats:sup>203\/212<\/jats:sup>Pb peptide-based radiopharmaceuticals for NET theranostics. These findings suggest that PSC-PEG<jats:sub>2<\/jats:sub>-TOC is a promising candidate for Pb-based targeted radionuclide therapy for NETs and other types of cancers that express SSTR2.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00259-023-06494-9","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T09:01:48Z","timestamp":1699866108000},"page":"1147-1162","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Structural modifications toward improved lead-203\/lead-212 peptide-based image-guided alpha-particle radiopharmaceutical therapies for neuroendocrine tumors"],"prefix":"10.1007","volume":"51","author":[{"given":"Dongyoul","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengshi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dijie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Baumhover","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin A.","family":"Sagastume","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenna M.","family":"Marks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prerna","family":"Rastogi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. 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