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

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

Methods: 250 mg Tl 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 Tl 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 Pb via the Tl(p,3n)Pb nuclear reaction. Following a cool-down period of >12 h, the target was removed and Tl dissolved in 4 M HNO. A NEPTIS Mosaic-LC synthesis unit performed automated separation using Eichrom Pb resin, and Pb was eluted using 8 M HCl or 1 M NHOAc. Tl was diverted to a vial for recovery in an electrolytic cell. Pb 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 Pb incorporation was verified by radio-TLC analysis.

Results: Cyclotron irradiations performed at 60 μA proton beam current and 23.3 MeV (Tl incident energy) had a Pb 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 [Pb]PbCl with a radionuclidic purity of >99.9 %. Purified [Pb]PbCl yields of up to 12 GBq Pb were attained (15.8 GBq at EOB). The [Pb]PbCl and [Pb]Pb(OAc) products contained no detectable radionuclidic impurities besides Pb (<0.1 %), and <0.4 ppm stable Pb. Tl metal was recovered with a 92 % batch yield. Aliquots of 100 μL [Pb]Pb(OAc) 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.

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

Advances In Knowledge And Implications For Patient Care: Our high-yield Pb production technique significantly enhances Pb production capabilities to meet the growing preclinical and clinical demand for Pb radiopharmaceuticals alongside Pb target alpha particle therapy.