Taking cyclotron 68Ga production to the next level: Expeditious solid target production of 68Ga for preparation of radiotracers

Abstract

Introduction: Gallium-68 is an important radionuclide for positron emission tomography (PET) with steadily increasing applications of ⁶⁸Ga-based radiopharmaceuticals for clinical use. Current ⁶⁸Ga sources are primarily ⁶⁸Ge/⁶⁸Ga-generators, along with successful attempts of ⁶⁸Ga production using a cyclotron. This study evaluated cyclotron ⁶⁸Ga production and automated separation using expeditiously manufactured solid targets, demonstrates an order of magnitude improvement in yield compared to ⁶⁸Ge/⁶⁸Ga generators, and presents a convenient alternative to existing cyclotron production processes. A comparison of radiolabeling and preclinical PET imaging was performed with both cyclotron and generator produced ⁶⁸Ga.

Methods: 100 mg enriched ⁶⁸Zn (99.3% ⁶⁸Zn, 0.48% ⁶⁷Zn, 0.1% ⁶⁶Zn) pellets pressed on silver discs were bombarded for 20-75 min using 12.5 MeV proton beam energies and 10-30 μA currents. ⁶⁸Ga was separated using an automated TRASIS AllinOne synthesizer employing AG 50W-X8 and UTEVA resins. Post-separation recovery of the ⁶⁸Zn by electrolysis yielded 76.7 ± 4.3%. Radionuclidic purity of cyclotron-produced ⁶⁸Ga was investigated with gamma spectroscopy using a HPGe-detector. Radiolabeling was investigated using the macrocyclic chelator DOTA and the bombesin-derived peptide NOTA-BBN2. PET imaging was performed using [⁶⁸Ga]Ga-NOTA-BBN2 in a PC3 xenograft model.

Results: 600 μA·min fresh and recycled quadruplet ⁶⁸Zn target irradiations (n = 8) at 12.5 MeV and 30 μA yielded 13.9 ± 1.0 GBq ⁶⁸Ga; 2200 μA·min irradiations (n = 3) yielded 37.5 ± 1.9 GBq ⁶⁸Ga. HPGe analysis showed EOB 0.0074% and 0.0084% of total activity of ⁶⁶Ga and ⁶⁷Ga, respectively. Metal impurities were 0.06 ± 0.03 μg/GBq Zn, 0.13 ± 0.007 μg/GBq Fe, and 0.02 ± 0.01 μg/GBq Al for cyclotron ⁶⁸Ga. Cyclotron and ⁶⁸Ge/⁶⁸Ga generator ⁶⁸Ga respective DOTA and NOTA-BBN2 labeling incorporations were 99.4 ± 0.0% and 99.3 ± 0.2%, and 90.4 ± 1.5% and 93.0 ± 3.6% determined by radio-thin layer chromatography (radio-TLC). Preclinical PET imaging comparison between generator and cyclotron produced ⁶⁸Ga showed identical radiotracer tumor uptake and biodistribution profiles in PC3 tumor bearing mice.

Conclusions: Cyclotron ⁶⁸Ga production provides highly scalable production with equivalent or superior quality ⁶⁸Ga to a ⁶⁸Ge/⁶⁸Ga generator, while providing identical biodistribution and tumor uptake profiles. Our described targetry is simpler and more cost-effective than existing liquid and solid targetry, enabling a turnkey production system for multi-facility distribution of cyclotron produced ⁶⁸Ga. The manufacturing simplicity described has potential applications for producing other radiometals such as ⁴⁴Sc.

Advances in knowledge and implications for patient care: Our cost-effective method of solid target ⁶⁸Ga production can enhance ⁶⁸Ga production capabilities to meet the high demand for ⁶⁸Ga-radiopharmaceuticals for research and clinical use.

Keywords: Cyclotron; Gallium-68; Positron emission tomography (PET); Radiotracer; Targetry.