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

Introduction: Gallium-68 is an important radionuclide for positron emission tomography (PET) with steadily increasing applications of Ga-68-based radiopharmaceuticals for clinical use. Current Ga-68 sources are primarily Ge-68-Ga-68-generators, along with successful attempts of Ga-68 production using a cyclotron. This study evaluated cyclotron Ga-68 production and automated separation using expeditiously manufactured solid targets, demonstrates an order of magnitude improvement in yield compared to Ge-68/Ga-68 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-68. Methods: 100 mg enriched Zn-68 (99.3% Zn-68, 0.48% Zn-67, 0.1% Zn-66) pellets pressed on silver discs were bombarded for 20-75 min using 12.5 MeV proton beam energies and 10-30 mu A currents. Ga-68 was separated using an automated TRASIS AllinOne synthesizer employing AG 50W-X8 and UTEVA resins. Post-separation recovery of the 68 Zn by electrolysis yielded 76.7 +/- 4.3%. Radionuclidic purity of cyclotron-produced Ga-68 was investigated with gamma spectroscopy using a HPGe-detector. Radiolabeling was investigated using the macrocydic chelator DOTA and the bombesin-derived peptide NOTA-BBN2. PET imaging was performed using [Ga-68]Ga-NOTA-BBN2 in a PC3 xenograft model. Results: 600 mu A.min fresh and recyded quadruplet Zn-68 target irradiations (n = 8) at 12.5 MeV and 30 mu A yielded 13.9 +/- 1.0 GBq Ga-68; 2200 mu A.min irradiations (n = 3) yielded 37.5 +/- 1.9 GBq Ga-68. HPGe analysis showed EOB 0.0074% and 0.0084% of total activity of Ga-66 and Ga-67, respectively. Metal impurities were 0.06 +/- 0.03 mu g/GBq Zn, 0.13 +/- 0.007 mu g/GBq Fe, and 0.02 +/- 0.01 mu g/GBq Al for cyclotron Ga-68. Cyclotron and Ge-68/Ga-68 generator Ga-68 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-68 showed identical radiotracer tumor uptake and biodistribution profiles in PC3 tumor bearing mice. Conclusions: Cyclotron Ga-68 production provides highly scalable production with equivalent or superior quality Ga-68 to a Ge-68/Ga-68 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-68. The manufacturing simplicity described has potential applications for producing other radiometals such as (SC)-S-44. Advances in knowledge and implications for patient care: Our cost-effective method of solid target Ga-68 production can enhance Ga-68 production capabilities to meet the high demand for Ga-68-radiopharmaceuticals for research and clinical use. (C) 2020 Elsevier Inc. All rights reserved.