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In this study, it was aimed to investigate 149 Tb-PSMA-617 for targeted α-therapy (TAT) using a mouse model of prostate-specific membrane antigen (PSMA)-expressing prostate cancer. 149 Tb-PSMA-617 was prepared with >98% radiochemical purity (6 MBq/nmol) for the treatment of mice with PSMA-positive PC-3 PIP tumors. 149 Tb-PSMA-617 was applied at 1 × 6 MBq (Day 0) or 2 × 3 MBq (Day 0 & Day 1 or Day 0 & Day 3) and the mice were monitored over time until they had reached a pre-defined endpoint which required euthanasia. The tumor growth was significantly delayed in mice of the treated groups as compared to untreated controls (p < 0.05). TAT was most effective in mice injected with 2 × 3 MBq (Day 0 & 1) resulting in a median lifetime of 36 days, whereas in untreated mice, the median lifetime was only 20 days. Due to the β + -emission of 149 Tb, tumor localization was feasible using PET/CT after injection of 149 Tb-PSMA-617 (5 MBq). The PET images confirmed the selective accumulation of 149 Tb-PSMA-617 in PC-3 PIP tumor xenografts. The unique characteristics of 149 Tb for TAT make this radionuclide of particular interest for future clinical translation, thereby, potentially enabling PET-based imaging to monitor the radioligand's tissue distribution.

Purpose: The prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate 161 Tb (T 1/2  = 6.89 days; Eβ ͞ av  = 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to 177 Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile., Methods: 161 Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol. 161 Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for 177 Lu-PSMA-617. The effects of 161 Tb-PSMA-617 and 177 Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. 161 Tb-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice., Results: 161 Tb-PSMA-617 and 177 Lu-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to 161 Tb-PSMA-617 as compared to the effect obtained with the same activities of 177 Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with 161 Tb-PSMA-617 (5.0 MBq/mouse and 10 MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65 days) compared to untreated control animals (19 days). Therapy studies to compare the effects of 161 Tb-PSMA-617 and 177 Lu-PSMA-617 indicated the anticipated superiority of 161 Tb over 177 Lu., Conclusion: 161 Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to 177 Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of 161 Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of 161 Tb-PSMA-617 for the treatment of mCRPC.

Currently, different radiometals are in use for imaging and therapy in nuclear medicine: 68 Ga and 111 In are examples of nuclides for positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively, while 177 Lu and 225 Ac are used for β - - and α-radionuclide therapy. The application of diagnostic and therapeutic radionuclides of the same element (radioisotopes) would utilize chemically-identical radiopharmaceuticals for imaging and subsequent treatment, thereby enabling the radiotheranostic concept. There are two elements which are of particular interest in this regard: Scandium and Terbium. Scandium presents three radioisotopes for theranostic application. 43 Sc (T 1/2 = 3.9 h) and 44 Sc (T 1/2 = 4.0 h) can both be used for PET, while 47 Sc (T 1/2 = 3.35 d) is the therapeutic match-also suitable for SPECT. Currently, 44 Sc is most advanced in terms of production, as well as with pre-clinical investigations, and has already been employed in proof-of-concept studies in patients. Even though the production of 43 Sc may be more challenging, it would be advantageous due to the absence of high-energetic γ-ray emission. The development of 47 Sc is still in its infancy, however, its therapeutic potential has been demonstrated preclinically. Terbium is unique in that it represents four medically-interesting radioisotopes. 155 Tb (T 1/2 = 5.32 d) and 152 Tb (T 1/2 = 17.5 h) can be used for SPECT and PET, respectively. Both radioisotopes were produced and tested preclinically. 152 Tb has been the first Tb isotope that was tested (as 152 Tb-DOTATOC) in a patient. Both radionuclides may be of interest for dosimetry purposes prior to the application of radiolanthanide therapy. The decay properties of 161 Tb (T 1/2 = 6.89 d) are similar to 177 Lu, but the coemission of Auger electrons make it attractive for a combined β - /Auger electron therapy, which was shown to be effective in preclinical experiments. 149 Tb (T 1/2 = 4.1 h) has been proposed for targeted α-therapy with the possibility of PET imaging. In terms of production, 161 Tb and 155 Tb are most promising to be made available at the large quantities suitable for future clinical translation. This review article is dedicated to the production routes, the methods of separating the radioisotopes from the target material, preclinical investigations and clinical proof-of-concept studies of Sc and Tb radionuclides. The availability, challenges of production and first (pre)clinical application, as well as the potential of these novel radionuclides for future application in nuclear medicine, are discussed.

The existence of theragnostic pairs of radionuclides allows the preparation of radiopharmaceuticals for diagnostic and therapeutic purposes. Radiolanthanides, such as 177 Lu, 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 152 Tb (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, 152 Tb 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 152 Tb 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. 152 Tb 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 152 Tb-labeled targeting agents has promise for clinical application and may be particularly interesting for pre-therapeutic dosimetry.

Introduction: We assessed the suitability of the radiolanthanide (155)Tb (t1/2=5.32 days, Eγ=87 keV (32%), 105keV (25%)) in combination with variable tumor targeted biomolecules using preclinical SPECT imaging., Methods: (155)Tb was produced at ISOLDE (CERN, Geneva, Switzerland) by high-energy (~1.4 GeV) proton irradiation of a tantalum target followed by ionization and on-line mass separation. (155)Tb was separated from isobar and pseudo-isobar impurities by cation exchange chromatography. Four tumor targeting molecules - a somatostatin analog (DOTATATE), a minigastrin analog (MD), a folate derivative (cm09) and an anti-L1-CAM antibody (chCE7) - were radiolabeled with (155)Tb. Imaging studies were performed in nude mice bearing AR42J, cholecystokinin-2 receptor expressing A431, KB, IGROV-1 and SKOV-3ip tumor xenografts using a dedicated small-animal SPECT/CT scanner., Results: The total yield of the two-step separation process of (155)Tb was 86%. (155)Tb was obtained in a physiological l-lactate solution suitable for direct labeling processes. The (155)Tb-labeled tumor targeted biomolecules were obtained at a reasonable specific activity and high purity (>95%). (155)Tb gave high quality, high resolution tomographic images. SPECT/CT experiments allowed excellent visualization of AR42J and CCK-2 receptor-expressing A431 tumors xenografts in mice after injection of (155)Tb-DOTATATE and (155)Tb-MD, respectively. The relatively long physical half-life of (155)Tb matched in particular the biological half-lives of (155)Tb-cm09 and (155)Tb-DTPA-chCE7 allowing SPECT imaging of KB tumors, IGROV-1 and SKOV-3ip tumors even several days after administration., Conclusions: The radiolanthanide (155)Tb may be of particular interest for low-dose SPECT prior to therapy with a therapeutic match such as the β(-)-emitting radiolanthanides (177)Lu, (161)Tb, (166)Ho, and the pseudo-radiolanthanide (90)Y., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unlabelled: Terbium offers 4 clinically interesting radioisotopes with complementary physical decay characteristics: (149)Tb, (152)Tb, (155)Tb, and (161)Tb. The identical chemical characteristics of these radioisotopes allow the preparation of radiopharmaceuticals with identical pharmacokinetics useful for PET ((152)Tb) and SPECT diagnosis ((155)Tb) and for α- ((149)Tb) and β(-)-particle ((161)Tb) therapy. The goal of this proof-of-concept study was to produce all 4 terbium radioisotopes and assess their diagnostic and therapeutic features in vivo when labeled with a folate-based targeting agent., Methods: (161)Tb was produced by irradiation of (160)Gd targets with neutrons at Paul Scherrer Institute or Institut Laue-Langevin. After neutron capture, the short-lived (161)Gd decays to (161)Tb. (149)Tb, (152)Tb, and (155)Tb were produced by proton-induced spallation of tantalum targets, followed by an online isotope separation process at ISOLDE/CERN. The isotopes were purified by means of cation exchange chromatography. For the in vivo studies, we used the DOTA-folate conjugate cm09, which binds to folate receptor (FR)-positive KB tumor cells. Therapy experiments with (149)Tb-cm09 and (161)Tb-cm09 were performed in KB tumor-bearing nude mice. Diagnostic PET/CT ((152)Tb-cm09) and SPECT/CT ((155)Tb-cm09 and (161)Tb-cm09) studies were performed in the same tumor mouse model., Results: Carrier-free terbium radioisotopes were obtained after purification, with activities ranging from approximately 6 MBq (for (149)Tb) to approximately 15 MBq (for (161)Tb). The radiolabeling of cm09 was achieved in a greater than 96% radiochemical yield for all terbium radioisotopes. Biodistribution studies showed high and specific uptake in FR-positive tumor xenografts (23.8% ± 2.5% at 4 h after injection, 22.0% ± 4.4% at 24 h after injection, and 18.4% ± 1.8% at 48 h after injection). Excellent tumor-to-background ratios at 24 h after injection (tumor to blood, ≈ 15; tumor to liver, ≈ 5.9; and tumor to kidney, ≈ 0.8) allowed the visualization of tumors in mice using PET ((152)Tb-cm09) and SPECT ((155)Tb-cm09 and (161)Tb-cm09). Compared with no therapy, α- ((149)Tb-cm09) and β(-)-particle therapy ((161)Tb-cm09) resulted in a marked delay in tumor growth or even complete remission (33% for (149)Tb-cm09 and 80% for (161)Tb-cm09) and a significantly increased survival., Conclusion: For the first time, to our knowledge, 4 terbium radionuclides have been tested in parallel with tumor-bearing mice using an FR targeting agent. Along with excellent tumor visualization enabled by (152)Tb PET and (155)Tb SPECT, we demonstrated the therapeutic efficacy of the α-emitter (149)Tb and β(-)-emitter (161)Tb.

Purpose: The β¯-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). Methods: The capability of the 161Tb- and 177Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides' tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. Results: In vitro, [161Tb]Tb-DOTA-LM3 was 102-fold more potent than [177Lu]Lu-DOTA-LM3; however, 161Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their 177Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [161Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [177Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. Conclusion: The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [161Tb]Tb-DOTA-LM3 may outperform the clinically employed [177Lu]Lu-DOTATOC for the treatment of patients with NENs. [ABSTRACT FROM AUTHOR]

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 (T1/2 = 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. [ABSTRACT FROM AUTHOR]

The decay of terbium-161 results in the emission of β¯-particles as well as conversion and Auger electrons, which makes terbium-161 interesting for therapeutic purposes. The aim of this study was to use dual-isotope SPECT imaging in order to demonstrate visually that terbium-161 and lutetium-177 are interchangeable without compromising the pharmacokinetic profile of the radiopharmaceutical. The 161Tb- and 177Lu-labeled somatostatin (SST) analogues DOTATOC (agonist) and DOTA-LM3 (antagonist) were tested in vitro to demonstrate equal properties regarding distribution coefficients and cell uptake into SST receptor-positive AR42J tumor cells. The radiopeptides were further investigated in AR42J tumor-bearing nude mice using the method of dual-isotope (terbium-161/lutetium-177) SPECT/CT imaging to enable the visualization of their distribution profiles in the same animal. Equal pharmacokinetic profiles were demonstrated for either of the two peptides, irrespective of whether it was labeled with terbium-161 or lutetium-177. Moreover, the visualization of the sub-organ distribution confirmed similar behavior of 161Tb- and 177Lu-labeled SST analogues. The data were verified in quantitative biodistribution studies using either type of peptide labeled with terbium-161 or lutetium-177. While the radionuclide did not have an impact on the organ distribution, this study confirmed previous data of a considerably higher tumor uptake of radiolabeled DOTA-LM3 as compared to the radiolabeled DOTATOC. [ABSTRACT FROM AUTHOR]