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

Pb-203 and Pb-212 have emerged as promising theranostic isotopes for image-guided alpha-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 Pb-212 at 25 degrees C and also to Bi-212 at 80 degrees C. Efficient radiolabeling of mixed Pb-212 and Bi-212 in PSC-PEG-T was also observed at 80 degrees C. Post radiolabeling, stable Pb(II) and Bi(III) radiometal complexes in saline were observed after incubating [Pb-203]Pb-PSC-PEG-T for 72 h and [Bi-212]Bi-PSC-PEG-T for 5 h. Stable [Pb-212]Pb-PSC-PEG-T and progeny [Bi-212]Bi-PSC-PEG-T were identified after storage in saline for 24 h. In serum, stable radiometal/radiopeptide were observed after incubating [Pb-203]Pb-PSC-PEG-T for 55 h and [Pb-212]Pb-PSC-PEG-T for 24 h. In vivo biodistribution of [Pb-212]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 Pb-212 and Bi-212, with no in vivo redistribution of progeny Bi-212. Single-photon emission computed tomography (SPECT) imaging of [Pb-203]Pb-PSC-PEG-T and [Pb-212]Pb-PSC-PEG-T in mice also demonstrated comparable accumulation in AR42J xenografts and renal clearance, confirming the theranostic potential of the elementally identical Pb-203/Pb-212 radionuclide pair.

Automated summary

A cyclen-based Pb-specific chelator (PSC) conjugated to tyr(3)-octreotide via a PEG(2) linker (PSC-PEG-T) was developed to target SSTR2. Efficient radiolabeling of purified Pb-212 and Bi-212 as well as mixed Pb-212 and Bi-212 in PSC-PEG-T was observed. Stable radiometal complexes were formed in saline and serum, and in vivo studies demonstrated the potential of [Pb-203]Pb-PSC-PEG-T and [Pb-212]Pb-PSC-PEG-T for tumor imaging.