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

Abstract

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.