¹⁶¹Tb-DOTATOC Production Using a Fully Automated Disposable Cassette System: A First Step Toward the Introduction of¹⁶¹Tb into the Clinic

Abstract

Tb is an interesting radionuclide for application in the treatment of neuroendocrine neoplasms' small metastases and single cancer cells because of its conversion and Auger-electron emission. Tb has coordination chemistry similar to that of Lu; therefore, like 177 Lu, it can stably radiolabel DOTATOC, one of the leading peptides used for the treatment of neuroendocrine neoplasms. However, 161 Tb is a recently developed radionuclide that has not yet been specified for clinical use. Therefore, the aim of the current work was to characterize and specify 161 Tb and to develop a protocol for the synthesis and quality control of 161 Tb-DOTATOC with a fully automated process conforming to goodmanufacturing-practice guidelines, in view of its clinical use. Methods: 161 Tb, produced by neutron irradiation of 160 Gd in high-flux reactors followed by radiochemical separation from its target material, was characterized regarding its radionuclidic purity, chemical purity, endotoxin level, and radiochemical purity (RCP) in analogy to what is described in the European Pharmacopoeia for no-carrier-added 177 Lu. In addition, 161 Tb was introduced into a fully automated cassette-module synthesis to produce 161 Tb-DOTATOC, as used for 177 Lu-DOTATOC. The quality and stability of the produced radiopharmaceutical in terms of identity, RCP, and ethanol and endotoxin content were assessed by means of high-performance liquid chromatography, gas chromatography, and an endotoxin test, respectively. Results: 161 Tb produced under the described conditions showed, as the no-carrier-added 177 Lu, a pH of 1-2, radionuclidic purity and RCP of more than 99.9%, and an endotoxin level below the permitted range (175 IU/mL), indicating its appropriate quality for clinical use. In addition, an efficient and robust procedure for the automated production and quality control of 161 Tb-DOTATOC with clinically applicable specifications and activity levels, that is, 1.0-7.4 GBq in 20 mL, was developed. The radiopharmaceutical's quality control was also developed using chromatographic methods, which confirmed the product's stability (RCP $ 95%) over 24 h. Conclusion: The current study demonstrated that 161 Tb has appropriate features for clinical use. The developed synthesis protocol guarantees high yields and safe preparation of injectable 161 Tb-DOTATOC. The investigated approach could be translated to other DOTA-derivatized peptides; thus, 161 Tb could be successfully applied in clinical practice for radionuclide therapy.

Radiolabelled 177Lu‐Bispidine‐Trastuzumab for Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancers

“…[5,6] Nevertheless, RIT is a promising alternative to traditional cancer treatment methods, particularly for patients where frontline chemotherapy fails or the disease stage precludes external beam treatment. [7] RIT offers the potential for precise damage to cancer cells through the emission of α-or β-particles from radionuclides, [8][9][10] which are often derived from heavier elements such as lanthanoids (e. g., 177 Lu 3 + (t 1/2 = 6.647 d, E β -(mean) = 133.7 keV, E β -(maximum) = 496.8 keV, total β-particle intensity I β = 100 %, mean β-particle dose D β (mean) = 0.1336 MeV/Bq-s), [2,10] 161 Tb (t 1/2 = 6.89 d, E β -(mean) = 154 keV, E β -(maximum) = 593.0 keV, total β-particle intensity I β = 100 %, mean β-particle dose D β (mean) = 0.156 MeV/Bq-s) [11,12] or actinides, notably 225 Ac (t 1/2 = 6.647 d, E α (maximum) = 5830 keV, total α-particle intensity I α = 100 %). [13] These metal ions possess distinct coordination chemistry compared to the more commonly used first-row d-block transition metals.…”