68Ga-DOTATATE Prepared from Cyclotron-Produced68Ga: An Integrated Solution from Cyclotron Vault to Safety Assessment and Diagnostic Efficacy in Neuroendocrine Cancer Patients

Cyclotron production of gallium-68 (68Ga) is a promising approach to supply 68Ga radiopharmaceuticals. To validate this capability, an integrated solution for a robust synthesis of 68Ga-DOTATATE prepared from cyclotron produced 68Ga (further on referred to as cyclotron produced 68Ga-DOTATATE) was achieved. A retrospective comparison analysis was performed in patients who underwent PET/CT imaging after injection of DOTATATE labeled with 68Ga produced by cyclotron or eluted from a generator to demonstrate the clinical safety and diagnostic efficacy of the radiopharmaceutical for a routine standard-of-care diagnostic tool in clinic. Methods: An enriched zinc-68 pressed target was irradiated by cyclotron with a proton beam set at 12.7 MeV for 100 min. The fully automated process utilizes an in-vault dissolution system where a liquid distribution system transfers the dissolved target to a dedicated hotcell for the purification of 68GaCl3 and radiolabeling of DOTATATE using a cassette-based automated module. Quality control tests were performed on the resulting tracer solution. The internal radiation dose for 68Ga-DOTATATE was calculated based on extrapolation from rat biodistribution experiments. A retrospective comparison analysis was performed in patients who underwent PET/CT imaging after injection of DOTATATE labeled with 68Ga produced by cyclotron or eluted from a generator. Results: The synthesis of 68Ga-DOTATATE (20.7 ± 1.3 GBq) with high apparent molar activity (518 ± 32 GBq/µmole at end of synthesis (EOS)) was completed in 65 min and the radiopharmaceutical met the requirements specified in the European Pharmacopeia monograph on Gallium (68Ga) chloride (accelerator produced) solution for radiolabeling. 68Ga-DOTATATE was stable for at least 5 h after formulation. The dosimetry calculated with OLINDA for 68Ga-DOTATATE from cyclotron produced 68Ga and generator eluted 68Ga was roughly equivalent. The SUVmean or SUVmax of tumoral lesions with cyclotron produced 68Ga-DOTATATE was equivalent to that with generator-eluted 68Ga. Among physiological uptakes, a significant difference was found in kidneys, spleen and stomach wall, with lower values in cyclotron produced 68Ga-DOTATATE in all cases. Conclusion: Integrated cyclotron production achieves reliable high yields of clinical-grade 68Ga-DOTATATE. The clinical safety, and imaging efficacy of cyclotron produced 68Ga-DOTATATE in humans provide supporting evidence for its use in routine clinical practice.