Abstract
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Objectives: We are currently performing a Phase-II, prospective, open label trial, to assess the safety of [68Ga]Ga-DOTA-TATE injection in patients with suspected or known tumors expressing somatostatin receptors. Since June 2016, more than 1000 patients underwent a [68Ga]Ga-DOTA-TATE PET/CT. 68Ga is currently produced via 68Ge/68Ga generator with limited lifetime restricting the number of patients per production. With the growing demand for this radiotracer, the need to significantly increase our 68Ga production capacity was required. This study focused on the validation of [68Ga]Ga-DOTA-TATE labeled with 68Ga produced by cyclotron using highly-enriched pressed zinc-68. We compared the chemical, radiochemical, and biological properties of cyclotron and generator-produced [68Ga]Ga-DOTA-TATE.
Methods: 68Ga was eluted from an IGG100 68Ge/68Ga generator (Eckert and Ziegler, EUROTOPE GmbH). 68Zn-pressed targets were irradiated 90 minutes at Ep 13 MeV and 35 μA. After purification, metal impurities in purified [68Ga]GaCl3 solution were identified by ICP-MS. DOTA-TATE (20 nmol) in high purity water was labeled with [68Ga]GaCl3 at 100 °C during 12 min and purified on Sep-Pak C18 cartridge. Quality control tests were performed on the resulting solution. The biodistribution patterns of the cyclotron- and 68Ge/68Ga generator-produced [68Ga]Ga-DOTA-TATE were determined in female Fisher rats.
Results: Up to 140 GBq of 68Ga was produced by cyclotron. Metallic impurities in purified [68Ga]GaCl3 were below the general limit of 10 ppm and 20 ppm for heavy metals in the US and Ph.Eur. The radiolabelling efficiency for [68Ga]Ga-DOTA-TATE was >95 %. Synthesis and QC tests were completed in 30 minutes and the radiopharmaceutical met all specifications. Cyclotron-produced [68Ga]Ga-DOTA-TATE showed significantly higher uptake in adrenals, an organ of interest rich in SST receptors, at early time points (15 and 30 min, p < 0.005) post-injection. Cyclotron- and generator produced [68Ga]Ga-DOTA-TATE were shown to be biologically equivalent at late time points, giving identical kinetic and biodistribution patterns in animals.
Conclusions: Our data indicate that a European Pharmacopoeia-compliant [68Ga]Ga-DOTA-TATE can be used as substitute of the generator derived 68Ga-radiopharmaceutical for nuclear imaging procedures.