Structural modifications toward improved lead-203/lead-212 peptide-based image-guided alpha-particle radiopharmaceutical therapies for neuroendocrine tumors

• DOI: 10.1007/s00259-023-06494-9
• Publication Date: 2023-11-13T09:01:48Z
• Authors: Dongyoul Lee; Mengshi Li; Dijie Liu; Nicholas J. Baumh...; Edwin A. Sagastume; Brenna M. Marks; Prerna Rastogi; F. Christopher Pigge; Yusuf Menda; Frances L. Johnson; Michael K. Schultz
• Keywords: Radionuclide therapy; Biodistribution; Conjugate; DOTA

Abstract Purpose The lead-203 ( 203 Pb)/lead-212 212 Pb) elementally identical radionuclide pair has gained significant interest in the field of image-guided targeted alpha-particle therapy for cancer. Emerging evidence suggests that Pb-labeled peptide-based radiopharmaceuticals targeting somatostatin receptor subtype 2 (SSTR2) may provide improved effectiveness compared to beta-particle-based therapies neuroendocrine tumors (NETs). This study aims improve performance SSTR2-targeted imaging and through structural modifications Tyr 3 -octreotide (TOC)-based radiopharmaceuticals. Methods New peptides were designed synthesized with goal optimizing incorporation Pb isotopes use a modified cyclization technique; introduction Pb-specific chelator (PSC); insertion polyethylene glycol (PEG) linkers. binding affinity cellular uptake evaluated using pancreatic AR42J (SSTR2+) tumor cells biodistribution assessed an xenograft mouse model. A lead peptide was identified (i.e., PSC-PEG -TOC), which then further efficacy studies. Results radiopeptide drug conjugate (RPDC) — [ Pb]Pb-PSC-PEG -TOC significantly tumor-targeting properties, including accumulation retention as Pb]Pb-DOTA 0 -Tyr (DOTATOC). Additionally, RPDC exhibited faster renal clearance than DOTATOC counterpart. These advantageous characteristics resulted dose-dependent therapeutic effect minimal signs toxicity Fractionated administrations 3.7 MBq over three doses anti-tumor effectiveness, resulting 80% survival (70% complete response) 120 days Conclusion Structural linker compositions pharmacokinetics (PK) 203/212 NET theranostics. findings suggest is promising candidate Pb-based NETs other types cancers express SSTR2.