Preclinical Evaluation of a Lead Specific Chelator (PSC) Conjugated to Radiopeptides for (203)Pb and (212)Pb-Based Theranostics

(203)Pb and (212)Pb have emerged as promising theranostic isotopes for image-guided α-particle radionuclide therapy for cancers. Here, we report a cyclen-based Pb specific chelator (PSC) that is conjugated to tyr(3)-octreotide via a PEG(2) linker (PSC-PEG-T) targeting somatostatin receptor subtype 2 (SSTR2). PSC-PEG-T could be labeled efficiently to purified (212)Pb at 25 °C and also to (212)Bi at 80 °C. Efficient radiolabeling of mixed (212)Pb and (212)Bi in PSC-PEG-T was also observed at 80 °C. Post radiolabeling, stable Pb(II) and Bi(III) radiometal complexes in saline were observed after incubating [(203)Pb]Pb-PSC-PEG-T for 72 h and [(212)Bi]Bi-PSC-PEG-T for 5 h. Stable [(212)Pb]Pb-PSC-PEG-T and progeny [(212)Bi]Bi-PSC-PEG-T were identified after storage in saline for 24 h. In serum, stable radiometal/radiopeptide were observed after incubating [(203)Pb]Pb-PSC-PEG-T for 55 h and [(212)Pb]Pb-PSC-PEG-T for 24 h. In vivo biodistribution of [(212)Pb]Pb-PSC-PEG-T in tumor-free CD-1 Elite mice and athymic mice bearing AR42J xenografts revealed rapid tumor accumulation, excellent tumor retention and fast renal clearance of both (212)Pb and (212)Bi, with no in vivo redistribution of progeny (212)Bi. Single-photon emission computed tomography (SPECT) imaging of [(203)Pb]Pb-PSC-PEG-T and [(212)Pb]Pb-PSC-PEG-T in mice also demonstrated comparable accumulation in AR42J xenografts and renal clearance, confirming the theranostic potential of the elementally identical (203)Pb/(212)Pb radionuclide pair.