Production of 203Pb from enriched 205Tl using deuteron beams.

Lead-203 is a SPECT emitter that can be used in theranostic applications as an imaging counterpart of lead-212 which is intended to be used for alpha therapy as lead-212/bismuth-212 in-vivo generator. In our study, we explore the production of lead-203 using enriched thallium-205 target irradiated by a deuteron beam. Excitation functions of deuteron induced reactions leading to the formation of 204m,203m2+m1+g,202m,201m+gPb, 202Tl and 203m+gHg isotopes were determined experimentally in the energy range from 21 MeV to 34 MeV. Cross sections were measured using the stacked foils technique and a set of two monitor foils, natNi and natTi for beam intensity evaluation. The experimental excitation functions of the investigated reactions were compared with the published data and also with the TENDL-2021 nuclear database. From our experimental data, we calculated lead-203 thick target yield in the energy range between 30 MeV and 32.5 MeV to be 56.7 MBq/µAh ±6.1 MBq/µAh. This value is compatible with large batch production showing that deuteron beams can be used for a routine production process. However, special attention must be paid to 203Hg and other lead contaminants.

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

(1) Background: In neuroendocrine tumors (NETs), somatostatin receptor subtype 2 is highly expressed, which can be targeted by a radioactive ligand such as [177Lu]Lu-1,4,7,10-tetraazacyclododecane-N,N',N″,N‴,-tetraacetic acid-[Tyr3,Thr8]-octreotide (177Lu-DOTA-TOC) and, more recently, by a lead specific chelator (PSC) containing 203/212Pb-PSC-PEG2-TOC (PSC-TOC). The molar activity (AM) can play a crucial role in tumor uptake, especially in receptor-mediated uptake, such as in NETs. Therefore, an investigation of the influence of different molar activities of 203/212Pb-PSC-TOC on cell uptake was investigated. (2) Methods: Optimized radiolabeling of 203/212Pb-PSC-TOC was performed with 50 µg of precursor in a NaAc/AcOH buffer at pH 5.3-5.5 within 15-45 min at 95° C. Cell uptake was studied in AR42 J, HEK293 sst2, and ZR75-1 cells. (3) Results: 203/212Pb-PSC-TOC was radiolabeled with high radiochemical purity >95% and high radiochemical yield >95%, with AM ranging from 0.2 to 61.6 MBq/nmol. The cell uptake of 203Pb-PSC-TOC (AM = 38 MBq/nmol) was highest in AR42 J (17.9%), moderate in HEK293 sstr (9.1%) and lowest in ZR75-1 (0.6%). Cell uptake increased with the level of AM. (4) Conclusions: A moderate AM of 15-40 MBq/nmol showed the highest cell uptake. No uptake limitation was found in the first 24-48 h. Further escalation experiments with even higher AM should be performed in the future. It was shown that AM plays an important role because of its direct dependence on the cellular uptake levels, possibly due to less receptor saturation with non-radioactive ligands at higher AM.

[212Pb]Pb-eSOMA-01: A Promising Radioligand for Targeted Alpha Therapy of Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) has been applied to the treatment of neuroendocrine tumors (NETs) for over two decades. However, improvement is still needed, and targeted alpha therapy (TAT) with alpha emitters such as lead-212 (212Pb) represents a promising avenue. A series of ligands based on octreotate was developed. Lead-203 was used as an imaging surrogate for the selection of the best candidate for the studies with lead-212. 203/212Pb radiolabeling and in vitro assays were carried out, followed by SPECT/CT imaging and ex vivo biodistribution in NCI-H69 tumor-bearing mice. High radiochemical yields (≥99%) and purity (≥96%) were obtained for all ligands. [203Pb]Pb-eSOMA-01 and [203Pb]Pb-eSOMA-02 showed high stability in PBS and mouse serum up to 24 h, whereas [203Pb]Pb-eSOMA-03 was unstable in those conditions. All compounds exhibited a nanomolar affinity (2.5-3.1 nM) for SSTR2. SPECT/CT images revealed high tumor uptake at 1, 4, and 24 h post-injection of [203Pb]Pb-eSOMA-01/02. Ex vivo biodistribution studies confirmed that the highest uptake in tumors was observed with [212Pb]Pb-eSOMA-01. [212Pb]Pb-eESOMA-01 displayed the highest absorbed dose in the tumor (35.49 Gy/MBq) and the lowest absorbed dose in the kidneys (121.73 Gy/MBq) among the three tested radioligands. [212Pb]Pb-eSOMA-01 is a promising candidate for targeted alpha therapy of NETs. Further investigations are required to confirm its potential.

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

[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.

Evaluation of a Novel Pb-203-Labeled Lactam-Cyclized Alpha-Melanocyte-Stimulating Hormone Peptide for Melanoma Targeting.

The purpose of this study is to examine the melanocortin-1 receptor (MC1R) targeting and specificity of 203Pb-DOTA-GGNle-CycMSHhex in melanoma cells and tumors to facilitate its potential therapeutic application when labeled with 212Pb. The MC1R-specific targeting and imaging properties of 203Pb-DOTA-GGNle-CycMSHhex were determined on B16/F1 and B16/F10 murine melanoma cells and in B16/F1 flank melanoma-, B16/F10 flank melanoma-, and B16/F10 pulmonary metastatic melanoma-bearing C57 mice. 203Pb-DOTA-GGNle-CycMSHhex displayed MC1R-specific binding on B16/F1 and B16/F10 melanoma cells and tumors. B16/F1 flank melanoma, B16/F10 flank melanoma, and B16/F10 pulmonary metastatic melanoma lesions could be clearly imaged by single photon emission computed tomography (SPECT) using 203Pb-DOTA-GGNle-CycMSHhex as an imaging probe. The favorable melanoma targeting and imaging properties highlighted the potential of 203Pb-DOTA-GGNle-CycMSHhex as a MC1R-targeting melanoma imaging probe and warranted the evaluation of 212Pb-DOTA-GGNle-CycMSHhex for melanoma therapy in future studies.

Incorporation of no-carrier added 200,203Pb and 200,201,202Tl in calcium alginate and hesperidin incorporated calcium alginate beads.

When radioisotopes are injected to human body, instantly free radicals are generated due to the interaction of ionizing radiation with water and fluids present in the body. The vehicle carrying radionuclides into human body should therefore be designed in a way which could also eliminate or reduce such possibilities. For the first time we have used free radical scavenger hesperidin, a polyphenolic compound having a benzo-γ-pyrone with a benzene ring moiety for extraction of no-carrier added (NCA) 200,203Pb and 200,201,202Tl. We have modified CA beads by incorporation of a polyphenol (hesperidin) (CA-Hes). This tailor made beads were characterized and tested for their efficacy towards extraction of no-carrier-added lead and thallium radioisotopes from 40MeV α particle irradiated Hg2Cl2 target.

Production and in vivo imaging of (203)Pb as a surrogate isotope for in vivo (212)Pb internal absorbed dose studies.

(212)Pb is a clinically relevant therapeutic alpha emitter isotope. A surrogate, (203)Pb, if prepared with sufficiently high specific activity could be used to estimate (212)Pb in vivo absorbed doses. An improved production procedure of (203)Pb with a simple, new separation method and high specific radioactivity for imaging is reported. We determined the in-vivo biodistribution of (203)Pb in mice by SPECT/CT. This highlights application possibilities of (203)Pb for further in vivo and clinical uses (radiolabeled (212)Pb-peptide co-injection, dosimetry calculation).

Evaluation of different production routes for the radio medical isotope ²°³Pb using TALYS 1.4 and EMPIRE 3.1 code calculations.

(203)Pb radio-medical isotope has found great field of applications in nuclear medicine over the last decades. The previously measured excitation functions for the production of this isotope from different reactions were discussed, in order to confirm the most reasonable ones. Fitting curves were given for some reactions leading to the production of this isotope. The theoretical models TALYS 1.4, and EMPIRE 3.1 were used to construct the excitation functions for protons, deuterons, helium-3 and helium-4 induced reactions on Tl and Hg targets. The results of different models were compared with each other as well as with the collected experimental results, using the mean weighted deviation (F), and the relative variance (D) statistical parameters. Thick target yields were estimated, based on the discussed excitation functions, and compared with some measured values.