Production, purification, and radiolabeling of the 203Pb/212Pb theranostic pair

Abstract

Background Lead-212 (212Pb, t1/2 = 10.6 h) and lead-203 (203Pb, t1/2 = 51.9 h) are an element-equivalent, or a matched theranostic radioisotope pair that show great potential for application in targeted radionuclide therapy (TRT) and single-photon emission computed tomography (SPECT), respectively. At TRIUMF we have produced both 203Pb and 212Pb using TRIUMF’s TR13 (13 MeV) and 500 MeV cyclotrons, and subsequently purified and evaluated both radioisotopes using a series of pyridine-modified DOTA analogues in comparison to the commercially available chelates DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and TCMC (1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane). Results Proton irradiation (12.8 MeV) of natural and enriched thallium-203 (203Tl) targets gave 203Pb saturation yields of 134 ± 25 and 483 ± 3 MBq/μA, respectively. Thorium-228 (228Th, t1/2 = 1.9 y), a by-product of 232Th proton spallation on TRIUMF’s main 500 MeV beamline (beamline 1A, BL1A), was recovered to build a 228Th/212Pb generator with the ability to deliver up to 9–10 MBq of 212Pb daily. Both lead isotopes were purified via solid phase extraction chromatography (Pb resin), and isolated in an acetate form ([203/212Pb]Pb(OAc)2) suitable for direct radiolabeling of chelators and bioconjugates. A series of cyclen-based chelators (herein referred to as DOTA-1Py, -2Py, and -3Py) along with established chelates DOTA and TCMC were evaluated for their ability to complex both 203Pb and 212Pb. All chelates incorporated 212Pb/203Pb efficiently, with higher radiolabeling yields observed for the 212Pb-complexes. Conclusion The production of 203Pb and 212Pb was established using TRIUMF 13 MeV and 500 MeV cyclotrons, respectively. Both production methods provided radiometals suitable for subsequent radiolabeling reactions using known and novel chelates. Furthermore, the novel chelate DOTA-3Py may be a good candidate for biomolecule conjugation and further theranostic 212Pb/203Pb studies.

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

“…Recently, cyclen-based macrocycles with pyridine arms were compared to the two standard of Pb(II) chelation. The structure DOTA-3Py showed similar results than DOTA or p -SCN-Bn-TCMC in terms of chelator concentration, RCYs as well as stability in human serum and emerged as a possible alternative for Pb(II) chelation [ 209 ].…”

The Evolving Coordination Chemistry of Radiometals for Targeted Alpha Therapy

“…[109] 228 Th produced from a 500 MeV cyclotron has been used to build a 228 Th/ 212 Pb generator with the ability to produce up to 10 MBq of 212 Pb daily. [110] Production of 203 Pb occurs through proton irradiation of naturally occurring thallium. [111] Lead Chemistry…”

“…[108,116] New chelators have been proposed for radiolabelling with Pb 2þ radionuclides such as pyridine-based cyclen derivatives that exhibited the ability to complex 212 Pb/ 203 Pb at ambient temperature at pH 7. [110] The coordination chemistry of the Pb 2þ complexes have not yet been reported. The Pb 2þ coordination chemistry of Me-dod2pa and the bis(semicarbazone) macrocyclic chelator have been investigated in detail.…”

“…Comparison of 203 Pb and 212 Pb radiolabelling reactions and chelator concentrations between 10 À4 and 10 À7 M. H 4 DOTA (RT, 1 h, pH7), p-SCN-Bn-TCMC (RT, 1 h, pH 7). Adapted from published sources [110].…”

Production and Supply of α-Particle–Emitting Radionuclides for Targeted α-Therapy

“…McNeil et al (61) reported the preparation of a novel 228 Th/ 212 Pb generator using 228 Th produced as a by-product of 232 Th spallation with 500-MeV protons at TRIUMF. The bulk thorium (8 g) (coprecipitated with 228 Th) was purified via anion exchange resin.…”