In recent years, ⁴⁷Sc has attracted attention because of its favorable decay characteristics (half-life, 3.35 d; average energy, 162 keV; Eγ, 159 keV) for therapeutic application and for SPECT imaging. The aim of the present study was to investigate the suitability of ⁴⁷Sc for radionuclide therapy in a preclinical setting. For this purpose a novel DOTA-folate conjugate (cm10) with an albumin-binding entity was used. Methods: ⁴⁷Sc was produced via the ⁴⁶Ca(n,γ)⁴⁷Ca ⁴⁷Sc nuclear reaction at the high-flux reactor at the Institut Laue-Langevin. Separation of the ⁴⁷Sc from the target material was performed by a semi-automated process using extraction chromatography and cation exchange chromatography. ⁴⁷Sc-labeled cm10 was tested on folate receptor–positive KB tumor cells in vitro. Biodistribution and SPECT imaging experiments were performed in KB tumor–bearing mice. Radionuclide therapy was conducted with two groups of mice, which received either ⁴⁷Sc-cm10 (10 MBq) or only saline. Tumor growth and survival time were compared between the two groups of mice. Results: Irradiation of ⁴⁶Ca resulted in approximately 1.8 GBq of ⁴⁷Ca, which subsequently decayed to ⁴⁷Sc. Separation of ⁴⁷Sc from ⁴⁷Ca was obtained with 80% yield in only 10 min. The ⁴⁷Sc was then available in a small volume (∼500 μL) of an ammonium acetate/HCl (pH 4.5) solution suitable for direct radiolabeling. ⁴⁷Sc-cm10 was prepared with a radiochemical yield of more than 96% at a specific activity of up to 13 MBq/nmol. In vitro ⁴⁷Sc-cm10 showed folate receptor–specific binding and uptake into KB tumor cells. In vivo SPECT/CT images allowed the visualization of accumulated radioactivity in KB tumors and in the kidneys. The therapy study showed a significantly delayed tumor growth in mice, which received ⁴⁷Sc-cm10 (10 MBq, 10 Gy) resulting in a more than 50% increase in survival time, compared with untreated control mice. Conclusion: With this study, we demonstrated the suitability of using ⁴⁷Sc for therapeutic purposes. On the basis of our recent results obtained with ⁴⁴Sc-folate, the present work confirms the applicability of ⁴⁴Sc/⁴⁷Sc as an excellent matched pair of nuclides for PET imaging and radionuclide therapy.

The targeting of the prostate-specific membrane antigen (PSMA) is of particular interest for radiotheragnostic purposes of prostate cancer. Radiolabeled PSMA-617, a 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA)-functionalized PSMA ligand, revealed favorable kinetics with high tumor uptake, enabling its successful application for PET imaging (68Ga) and radionuclide therapy (177Lu) in the clinics. In this study, PSMA-617 was labeled with cyclotron-produced 44Sc (T 1/2 = 4.04 h) and investigated preclinically for its use as a diagnostic match to 177Lu-PSMA-617. 44Sc was produced at the research cyclotron at PSI by irradiation of enriched 44Ca targets, followed by chromatographic separation. 44Sc-PSMA-617 was prepared under standard labeling conditions at elevated temperature resulting in a radiochemical purity of >97% at a specific activity of up to 10 MBq/nmol. 44Sc-PSMA-617 was evaluated in vitro and compared to the 177Lu- and 68Ga-labeled match, as well as 68Ga-PSMA-11 using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu prostate cancer cells. In these experiments it revealed similar in vitro properties to that of 177Lu- and 68Ga-labeled PSMA-617. Moreover, 44Sc-PSMA-617 bound specifically to PSMA-expressing PC-3 PIP tumor cells, while unspecific binding to PC-3 flu cells was not observed. The radioligands were investigated with regard to their in vivo properties in PC-3 PIP/flu tumor-bearing mice. 44Sc-PSMA-617 showed high tumor uptake and a fast renal excretion. The overall tissue distribution of 44Sc-PSMA-617 resembled that of 177Lu-PSMA-617 most closely, while the 68Ga-labeled ligands, in particular 68Ga-PSMA-11, showed different distribution kinetics. 44Sc-PSMA-617 enabled distinct visualization of PC-3 PIP tumor xenografts shortly after injection, with increasing tumor-to-background contrast over time while unspecific uptake in the PC-3 flu tumors was not observed. The in vitro characteristics and in vivo kinetics of 44Sc-PSMA-617 were more similar to 177Lu-PSMA-617 than to 68Ga-PSMA-617 and 68Ga-PSMA-11. Due to the almost four-fold longer half-life of 44Sc as compared to 68Ga, a centralized production of 44Sc-PSMA-617 and transport to satellite PET centers would be feasible. These features make 44Sc-PSMA-617 particularly appealing for clinical application.

149Tb represents a powerful alternative to currently used α-emitters: the relatively short half-life (T1/2 = 4.1 h), low α-energy (3.97 MeV, Iα = 16.7 %), absence of α-emitting daughters and stable coordination via DOTA are favorable features for potential clinical application. In this letter, we wish to highlight the unique characteristics of 149Tb for PET imaging, based on its positron emission (Eβ+mean = 730 keV, Iβ+ = 7.1 %) in addition to it’s a therapeutic value. To this end, a preclinical study with a tumor-bearing mouse is presented. The perspective of alpha-PET makes 149Tb highly appealing for radiotheragnostic applications in future clinical trials.

161Tb is an interesting radionuclide for cancer treatment, showing similar decay characteristics and chemical behavior to clinically-employed 177Lu. The therapeutic effect of 161Tb, however, may be enhanced due to the co-emission of a larger number of conversion and Auger electrons as compared to 177Lu. The aim of this study was to produce 161Tb from enriched 160Gd targets in quantity and quality sufficient for first application in patients. No-carrier-added 161Tb was produced by neutron irradiation of enriched 160Gd targets at nuclear research reactors. The 161Tb purification method was developed with the use of cation exchange (Sykam resin) and extraction chromatography (LN3 resin), respectively. The resultant product (161TbCl3) was characterized and the 161Tb purity compared with commercial 177LuCl3. The purity of the final product (161TbCl3) was analyzed by means of γ-ray spectrometry (radionuclidic purity) and radio TLC (radiochemical purity). The radiolabeling yield of 161Tb-DOTA was assessed over a two-week period post processing in order to observe the quality change of the obtained 161Tb towards future clinical application. To understand how the possible drug products (peptides radiolabeled with 161Tb) vary with time, stability of the clinically-applied somatostatin analogue DOTATOC, radiolabeled with 161Tb, was investigated over a 24-h period. The radiolytic stability experiments were compared to those performed with 177Lu-DOTATOC in order to investigate the possible influence of conversion and Auger electrons of 161Tb on peptide disintegration. Irradiations of enriched 160Gd targets yielded 6–20 GBq 161Tb. The final product was obtained at an activity concentration of 11–21 MBq/μL with ≥99% radionuclidic and radiochemical purity. The DOTA chelator was radiolabeled with 161Tb or 177Lu at the molar activity deemed useful for clinical application, even at the two-week time point after end of chemical separation. DOTATOC, radiolabeled with either 161Tb or 177Lu, was stable over 24 h in the presence of a stabilizer. In this study, it was shown that 161Tb can be produced in high activities using different irradiation facilities. The developed method for 161Tb separation from the target material yielded 161TbCl3 in quality suitable for high-specific radiolabeling, relevant for future clinical application.

The existence of theragnostic pairs of radionuclides allows the preparation of radiopharmaceuticals for diagnostic and therapeutic purposes. Radiolanthanides, such as ¹⁷⁷Lu, are successfully used for therapeutic purposes; however, a perfect diagnostic match is currently not available for clinical use. A unique, multi-disciplinary study was performed using ¹⁵²Tb (T_1/2 = 17.5 h, Eβ⁺ _average = 1140 keV, Iβ⁺ = 20.3%), which resulted in the first-in-human PET/CT images with this promising radionuclide. For this purpose, ¹⁵²Tb was produced via a spallation process followed by mass separation at ISOLDE, CERN. The chemical separation and quality control, performed at PSI, resulted in a pure product in sufficient yields. Clinical PET phantom studies revealed an increased image noise level, because of the smaller β⁺ branching ratio of ¹⁵²Tb as compared to standard PET nuclides at matched activity concentrations; however, the expected recovery would be comparable at matched signal-to-noise ratios in clinical PET. ¹⁵²Tb was used for labeling DOTATOC, at Zentralklinik Bad Berka, and administered to a patient for a first-in-human clinical study. PET scans were performed over a period of 24 h, allowing the visualization of even small metastases with increased tumor-to-background contrast over time. Based on the results obtained in this work, it can be deduced that PET/CT imaging with ¹⁵²Tb-labeled targeting agents has promise for clinical application and may be particularly interesting for pre-therapeutic dosimetry.