Dosimetry of [212Pb]VMT01, a MC1R-Targeted Alpha Therapeutic Compound, and Effect of Free 208Tl on Tissue Absorbed Doses

Abstract

[212Pb]VMT01 is a melanocortin 1 receptor (MC1R) targeted theranostic ligand in clinical development for alpha particle therapy for melanoma. 212Pb has an elementally matched gamma-emitting isotope 203Pb; thus, [203Pb]VMT01 can be used as an imaging surrogate for [212Pb]VMT01. [212Pb]VMT01 human serum stability studies have demonstrated retention of the 212Bi daughter within the chelator following beta emission of parent 212Pb. However, the subsequent alpha emission from the decay of 212Bi into 208Tl results in the generation of free 208Tl. Due to the 10.64-hour half-life of 212Pb, accumulation of free 208Tl in the injectate will occur. The goal of this work is to estimate the human dosimetry for [212Pb]VMT01 and the impact of free 208Tl in the injectate on human tissue absorbed doses. Human [212Pb]VMT01 tissue absorbed doses were estimated from murine [203Pb]VMT01 biodistribution data, and human biodistribution values for 201Tl chloride (a cardiac imaging agent) from published data were used to estimate the dosimetry of free 208Tl. Results indicate that the dose-limiting tissues for [212Pb]VMT01 are the red marrow and the kidneys, with estimated absorbed doses of 1.06 and 8.27 mGyRBE = 5/MBq. The estimated percent increase in absorbed doses from free 208Tl in the injectate is 0.03% and 0.09% to the red marrow and the kidneys, respectively. Absorbed doses from free 208Tl result in a percent increase of no more than 1.2% over [212Pb]VMT01 in any organ or tissue. This latter finding indicates that free 208Tl in the [212Pb]VMT01 injectate will not substantially impact estimated tissue absorbed doses in humans.

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

“…On the other hand, the impact from free 208 Tl is also very minimal. The recoiled free 208 Tl from alpha emission of 212 Bi results in 0.03% and 0.09% increase in the absorbed dose to the red marrow and the kidneys, respectively [ 55 ]. In general, free 208 Tl results in less than 1.2% absorbed dose in any organ or tissue [ 55 ].…”

“…The recoiled free 208 Tl from alpha emission of 212 Bi results in 0.03% and 0.09% increase in the absorbed dose to the red marrow and the kidneys, respectively [ 55 ]. In general, free 208 Tl results in less than 1.2% absorbed dose in any organ or tissue [ 55 ]. In the micro-SPECT imaging study, the Bioemtech Gamma-Eye SPECT Imaging system had energy range of 30–500 keV.…”

Influence of the Molar Activity of 203/212Pb-PSC-PEG2-TOC on Somatostatin Receptor Type 2-Binding and Cell Uptake

“…Isothermal titration calorimetry (ITC) experiments confirmed the stability of the 212 Bi daughter radionuclide in the PSC chelator to >95% at 2 h after radiolabeling. Importantly, the contribution of free 208 Tl to the total body dose was shown to be negligible [20]. The optimization of the radiochemical labeling procedure included steps to overcome the loss of activity due to several purification steps: The freshly eluted activity from the 224 Ra/ 212 Pb generator is partitioned into Pb resin 10-12%, waste ~2%, and product 84-86%.…”