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

INTRODUCTION

Gallium-68 is an important radionuclide for positron emission tomography (PET) with steadily increasing applications of Ga-based radiopharmaceuticals for clinical use. Current Ga sources are primarily Ge/Ga-generators, along with successful attempts of Ga production using a cyclotron. This study evaluated cyclotron Ga production and automated separation using expeditiously manufactured solid targets, demonstrates an order of magnitude improvement in yield compared to Ge/Ga 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 Ga.

METHODS

100 mg enriched Zn (99.3% Zn, 0.48% Zn, 0.1% Zn) pellets pressed on silver discs were bombarded for 20-75 min using 12.5 MeV proton beam energies and 10-30 μA currents. Ga was separated using an automated TRASIS AllinOne synthesizer employing AG 50W-X8 and UTEVA resins. Post-separation recovery of the Zn by electrolysis yielded 76.7 ± 4.3%. Radionuclidic purity of cyclotron-produced Ga 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 [Ga]Ga-NOTA-BBN2 in a PC3 xenograft model.

RESULTS

600 μA·min fresh and recycled quadruplet Zn target irradiations (n = 8) at 12.5 MeV and 30 μA yielded 13.9 ± 1.0 GBq Ga; 2200 μA·min irradiations (n = 3) yielded 37.5 ± 1.9 GBq Ga. HPGe analysis showed EOB 0.0074% and 0.0084% of total activity of Ga and Ga, 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 Ga. Cyclotron and Ge/Ga generator Ga 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 Ga showed identical radiotracer tumor uptake and biodistribution profiles in PC3 tumor bearing mice.

CONCLUSIONS

Cyclotron Ga production provides highly scalable production with equivalent or superior quality Ga to a Ge/Ga 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 Ga. The manufacturing simplicity described has potential applications for producing other radiometals such as Sc.

ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE

Our cost-effective method of solid target Ga production can enhance Ga production capabilities to meet the high demand for Ga-radiopharmaceuticals for research and clinical use.