High-yield cyclotron production of ²⁰³Pb using a sealed ²⁰⁵Tl solid target

²⁰³Pb (t_1/2 = 51.9 h, 279 keV (81 %)) is a diagnostic SPECT imaging radionuclide ideally suited for theranostic applications in combination with ²¹²Pb for targeted alpha particle therapy. Our objectives were to develop a high-yield solid target ²⁰³Pb cyclotron production route using isotopically enriched ²⁰⁵Tl target material and the ²⁰⁵Tl(p,3n)²⁰³Pb reaction as an alternative to lower energy production via the ²⁰³Tl(p,n)²⁰³Pb reaction.

250 mg ²⁰⁵Tl metal (99.9 % isotopic enrichment) was pressed using a hardened stainless steel die. Aluminum target discs were machined with a central depression and annulus groove. The flattened ²⁰⁵Tl pellet was placed into the central depression of the Al disc and a circle of indium wire was laid in the machined annulus surrounding the pellet. An aluminum foil cover was then pressed onto the target disc to create an airtight bond. Targets were irradiated at 23.3 MeV for up to 516 min on a TR-24 cyclotron at currents up to 60 μA to produce ²⁰³Pb via the ²⁰⁵Tl(p,3n)²⁰³Pb nuclear reaction. Following a cool-down period of >12 h, the target was removed and ²⁰⁵Tl dissolved in 4 M HNO₃. A NEPTIS Mosaic-LC synthesis unit performed automated separation using Eichrom Pb resin, and ²⁰³Pb was eluted using 8 M HCl or 1 M NH₄OAc. ²⁰⁵Tl was diverted to a vial for recovery in an electrolytic cell. ²⁰³Pb product radionuclidic purity was assessed by HPGe gamma spectroscopy, while elemental purity was assessed by ICP-OES. Radiolabeling and stability studies were performed with PSC, TCMC, and DOTA chelators, and ²⁰³Pb incorporation was verified by radio-TLC analysis.

Cyclotron irradiations performed at 60 μA proton beam current and 23.3 MeV (²⁰⁵Tl incident energy) had a ²⁰³Pb saturated yield of 4658 ± 62 MBq/μA (n = 3). Automated NEPTIS separation took <4 h from the start of target dissolution to product elution, yielding >85 % decay-corrected [²⁰³Pb]PbCl₂ with a radionuclidic purity of >99.9 %. Purified [²⁰³Pb]PbCl₂ yields of up to 12 GBq ²⁰³Pb were attained (15.8 GBq at EOB). The [²⁰³Pb]PbCl₂ and [²⁰³Pb]Pb(OAc)₂ products contained no detectable radionuclidic impurities besides ²⁰¹Pb (<0.1 %), and <0.4 ppm stable Pb. ²⁰⁵Tl metal was recovered with a 92 % batch yield. Aliquots of 100 μL [²⁰³Pb]Pb(OAc)₂ were used for radiolabeling PSC-Bn-NCS, TCMC-NCS, and DOTA-NCS chelators at pH 4.5 and 22 °C for 30 min, with maximum respective molar activities of 461 ± 30 GBq/μmol, 195 ± 37 GBq/μmol, and 83 ± 12 GBq/μmol. PSC, TCMC, and DOTA chelators exhibited >99.9 % incorporation after a 120-hour incubation in human serum at 37 °C.

Nuclear medicine centers with access to higher energy cyclotrons can produce large ²⁰³Pb activities sufficient for clinical applications, with a convenient separation technique producing highly pure [²⁰³Pb]PbCl₂ or [²⁰³Pb]Pb(OAc)₂ for direct radiolabeling. This represents an attractive route to produce ²⁰³Pb for diagnostic SPECT imaging alongside ²¹²Pb targeted alpha particle therapy.

Our high-yield ²⁰³Pb production technique significantly enhances ²⁰³Pb production capabilities to meet the growing preclinical and clinical demand for ²⁰³Pb radiopharmaceuticals alongside ²¹²Pb target alpha particle therapy.