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

Lead-212 (²¹²Pb, t_1/2 = 10.6 h) and lead-203 (²⁰³Pb, t_1/2 = 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).

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, t_1/2 = 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.

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.