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

Abstract

203Pb and 212Pb 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 tyr3-octreotide via a PEG2 linker (PSC-PEG-T) targeting somatostatin receptor subtype 2 (SSTR2). PSC-PEG-T could be labeled efficiently to purified 212Pb at 25 °C and also to 212Bi at 80 °C. Efficient radiolabeling of mixed 212Pb and 212Bi 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 [203Pb]Pb-PSC-PEG-T for 72 h and [212Bi]Bi-PSC-PEG-T for 5 h. Stable [212Pb]Pb-PSC-PEG-T and progeny [212Bi]Bi-PSC-PEG-T were identified after storage in saline for 24 h. In serum, stable radiometal/radiopeptide were observed after incubating [203Pb]Pb-PSC-PEG-T for 55 h and [212Pb]Pb-PSC-PEG-T for 24 h. In vivo biodistribution of [212Pb]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 212Pb and 212Bi, with no in vivo redistribution of progeny 212Bi. Single-photon emission computed tomography (SPECT) imaging of [203Pb]Pb-PSC-PEG-T and [212Pb]Pb-PSC-PEG-T in mice also demonstrated comparable accumulation in AR42J xenografts and renal clearance, confirming the theranostic potential of the elementally identical 203Pb/212Pb radionuclide pair.

Pre-clinical Evaluation of Biomarkers for Early Detection of Nephrotoxicity Following Alpha-particle Radioligand Therapy

“…[ 203 Pb]Pb-MC1L surrogate was injected in the same animal model to determine the in vivo biodistribution for calculating the dosimetry of [ 203 Pb]Pb-MC1L in normal organs. Our prior studies have demonstrated excellent chelation kinetics and stability with PSC for [ 212 Pb] and [ 212 Bi][8]. However previous literature has shown that during a fraction of [ 212 Pb] disintegrations, the daughter [ 212 Bi] cations are released from the chelator[25].…”

“…Among commercially available α-emitters, [ 212 Pb] (half-life T 1/2 10.6 h) is produced using a [ 224 Ra]/[ 212 Pb] generator system that enables nimble on-demand production of [ 212 Pb]Pb-based radiopharmaceuticals[7]. In the case of [ 212 Pb], the isotope [ 203 Pb] (T 1/2 51.9 h) can be used as a single-photon emission computerized tomography (SPECT) imaging diagnostic companion to provide detailed dosimetry that guides [ 212 Pb] therapy dosing [8]. The [ 203 Pb]/[ 212 Pb] radionuclide pair has the advantage that elementally identical imaging surrogate [ 203 Pb] can guide [ 212 Pb] therapy ( Figure 1b ).…”

Towards Effective Targeted Alpha Therapy for Neuroendocrine Tumours: A Review

“…This may be less so with the use of relatively short-lived 212 Pb because the recoil energy of the β-particle emission of 212 Pb is significantly less than the binding energy of the daughter nucleus to the chelator. Although reports of Bi instability to decoupling has been reported for DOTA and TCMC [ 44 , 45 ], recent reports of a new chelator with improved stability of the chelator 212 Bi coupling represents an advance that can improve the therapeutic index for targeting ligands conjugated to this new chelator (known as Pb-Specific-Chelator or PSC) [ 46 , 47 , 48 , 49 ].…”

Charting the Course of Targeted α Therapy With First-in-Human, Postadministration Image-Guided Dosimetry and Response Assessment of 212Pb-VMT-α-NET in Metastatic Neuroendocrine Tumors

“…[2][3][4][5] VMT-α-peptide, a novel molecule which targets the somatostatin receptor subtype-2 (SSTR2), has demonstrated promising results in preclinical studies for targeted α therapy in Neuroendocrine Tumors (NETs). 6…”

“…Ongoing research, both preclinical and clinical, is actively investigating the use of peptides and antibodies labeled with 212 Pb 2–5 . VMT-α-peptide, a novel molecule which targets the somatostatin receptor subtype-2 (SSTR2), has demonstrated promising results in preclinical studies for targeted α therapy in Neuroendocrine Tumors (NETs) 6 . SPECT/CT imaging with 212 Pb VMT-α-NET has shown immediate tumor accumulation, high tumor retention, and rapid renal excretion, indicating its potential effectiveness as seen in our case.…”