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The favorable decay characteristics of 161 Tb attracted the interest of clinicians in using this novel radionuclide for radioligand therapy (RLT). 161 Tb decays with a similar half-life to 177 Lu, but beyond the emission of β - -particles and γ-rays, 161 Tb also emits conversion and Auger electrons, which may be particularly effective to eliminate micrometastases. The aim of this study was to compare the dosimetry and therapeutic efficacy of 161 Tb and 177 Lu in tumor-bearing mice using SibuDAB and PSMA-I&T, which differ in their blood residence time and tumor uptake. Methods: [ 161 Tb]Tb-SibuDAB and [ 161 Tb]Tb-PSMA-I&T were evaluated in vitro and investigated in biodistribution, imaging, and therapy studies using PC-3 PIP tumor-bearing mice. The 177 Lu-labeled counterparts served for dose calculations and comparison of therapeutic efficacy. The tolerability of RLT in mice was monitored on the basis of body mass, blood plasma parameters, blood cell counts, and the histology of relevant organs and tissues. Results: The prostate-specific membrane antigen (PSMA)-targeting radioligands, irrespective of whether labeled with 161 Tb or 177 Lu, showed similar in vitro data and comparable tissue distribution profiles. As a result of the albumin-binding properties, [ 161 Tb]Tb/[ 177 Lu]Lu-SibuDAB had an enhanced blood residence time and higher tumor uptake (62%-69% injected activity per gram at 24 h after injection) than [ 161 Tb]Tb/[ 177 Lu]Lu-PSMA-I&T (30%-35% injected activity per gram at 24 h after injection). [ 161 Tb]Tb-SibuDAB inhibited tumor growth more effectively than [ 161 Tb]Tb-PSMA-I&T, as can be ascribed to its 4-fold increased absorbed tumor dose. At any of the applied activities, the 161 Tb-based radioligands were therapeutically more effective than their 177 Lu-labeled counterparts, as agreed with the approximately 40% increased tumor dose of 161 Tb compared with that of 177 Lu. Under the given experimental conditions, no obvious adverse events were observed. Conclusion: The data of this study indicate the promising potential of 161 Tb in combination with SibuDAB for RLT of prostate cancer. Future clinical studies using 161 Tb-based RLT will shed light on a potential clinical benefit of 161 Tb over 177 Lu., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog 177 Lu-DOTA-(d-Glu) 6 -Ala-Tyr-Gly-Trp-Nle-Asp-PheNH 2 ( 177 Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (∼80 μg) of 177 Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of 177 Lu-PP-F11N to assess safety. Results: In all patients, 177 Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85-1.04), 0.42 (IQR: 0.25-1.01), 0.11 (IQR: 0.07-0.13), and 0.028 (IQR: 0.026-0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11-14.4) without SG and 13.0 (IQR: 10.2-18.6) with SG; these values were not significantly different ( P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14-4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion: 177 Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, 177 Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of 177 Lu-PP-F11N., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

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.

Background: Protein kinase inhibitors (PKIs) are currently tested in clinical studies (phase I-III) as an alternative strategy against (recurrent) ovarian cancer. Besides their anti-tumour efficacy, several PKIs have also shown radiosensitizing effects when combined with external beam radiation. Based on these results we asked if the addition of PKIs offers a therapeutic opportunity to improve radioimmunotherapy (RIT) against ovarian cancer. Five PKIs (alisertib, MK1775, MK2206, saracatinib, temsirolimus) were chosen for cytotoxicity screenings based on their current clinical trials in the treatment of ovarian cancer and their influence on cell cycle regulation and DNA damage repair pathways. We combined selected PKIs with 177 Lu-labelled anti-L1CAM monoclonal antibody chCE7 for our investigations., Methods: PKIs cytotoxicity was determined via cell colony-forming assays. Biomarker of DNA double-strand breaks (DSBs, γH2A.X) was analysed by western blot and fluorescence microscopy. Flow cytometric measurements were performed to evaluate levels of apoptosis based on mono- or combination treatments. The best combination was used for in vivo combination therapy studies in nude mice with SKOV3ip and IGROV1 human ovarian cancer xenografts. Bonferroni correction was used to determine statistical significance for multiple comparisons., Results: The highest cytotoxicity against both cell lines was observed for MK1775 and alisertib. Combinations including 177 Lu-labelled mAb chCE7 and MK1775 decreased 177 Lu-DOTA-chCE7 IC 60 -values 14-fold, compared to 6-fold, when the radioimmunoconjugate was combined with alisertib. The most effective PKI MK1775 was further evaluated and demonstrated synergistic effects in combination with 177 Lu-DOTA-chCE7 against IGROV1 cells. Significantly higher amounts of DSBs were detected in IGROV1 cells after combination (91%) compared to either treatment alone (MK1775: 52%; radioimmunoconjugate: 72%; p < 0.0125). Early-apoptosis was significantly enhanced in IGROV1 cells correlating with induced DSBs ( 177 Lu-DOTA-chCE7: 8%, MK1775: 28%, 177 Lu-DOTA-chCE7 + MK1775: 40%, p < 0.0125). Immunohistochemistry analysis of γH2A.X expression levels after therapy in SKOV3ip xenografts revealed a high sensitivity of the tumour cells to MK1775 and a high radioresistance. A prominent effect of tumour growth inhibition of the RIT and of the combination therapy was observed in vivo in a late stage IGROV1 xenograft model., Conclusions: Our results warrant further evaluation of combination of MK1775 and radioimmunotherapy.

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.

In recent years, new α-particle-, β - -particle-, and Auger electron-emitting radiometals-such as 67 Cu, 47 Sc, 166 Ho, 161 Tb, 149 Tb, 212 Pb/ 212 Bi, 225 Ac, and 213 Bi-have been produced and evaluated (pre)clinically for therapeutic purposes. In this short review article, the most important routes of production of these radiometals are critically discussed, as are examples of their application in preclinical and clinical studies., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Tumor targeting with folic acid radioconjugates has been proposed as a promising strategy for radionuclide therapy of folate receptor α (FR)-positive cancer. Recently, it was shown that modification of radiofolates with an albumin-binding entity increased the tumor-to-kidney ratios of accumulated radioactivity in mice. The goal of this study was to evaluate the lead compound cm10 and compare it with new albumin-binding folate conjugates. Compound cm12 was designed with a long spacer consisting of a PEG-11 entity, and compound cm13 contained a short alkane chain between the albumin-binding moiety and folic acid. All of the derivatives were labeled with 177 Lu (t 1/2 = 6.65 days, E β - ,average = 134 keV; E γ = 113 keV, 208 keV), a clinically established radionuclide for therapeutic purposes. The evaluation revealed that all of the albumin-binding radiofolates exhibited increased in vitro stability compared with the reference compound ( 177 Lu-cm14) without albumin binder. Serum protein binding, determined with an ultrafiltration assay, was high (>88%) for the derivatives with albumin-binding entities. The FR-binding affinity was in the same range (K D = 4.0-7.5 nM) for all of the radiofolates, independent of the albumin-binding entity and spacer length. FR-specific uptake was proven in vitro using FR-positive KB tumor cells. In vivo studies with KB-tumor-bearing mice were performed in order to assess the tissue distribution profile of the novel radiofolates. 177 Lu-cm13 showed high tumor uptake at late time points (13.3 ± 2.94% IA/g, 48 h p.i.) and tumor-to-kidney ratios (0.59 ± 0.03, 48 h p.i.) in the same range as 177 Lu-cm10 (0.55 ± 0.07, 48 h p.i.). However, the tumor-to-kidney ratio of 177 Lu-cm12 (0.28 ± 0.07, 48 h p.i.) was reduced compared with 177 Lu-cm10 and 177 Lu-cm13. The results of this study indicate that the spacer entity between folic acid and the albumin binder is of critical importance with regard to the tissue distribution profile of the radiofolate. The PEG spacer compromised the beneficial effects of the lead compound, but the design with a short alkane spacer appeared to be promising. Future studies will focus on the design of radiofolates with lipophilic and more rigid spacer entities, which may allow a further improvement of their tissue distribution profiles.

Introduction: Affibody molecules are small (58 amino acids) high-affinity proteins based on a tri-helix non-immunoglobulin scaffold. A clinical study has demonstrated that PET imaging using Affibody molecules labeled with 68 Ga (T ½ =68min) can visualize metastases of breast cancer expressing human epidermal growth factor receptor type 2 (HER2) and provide discrimination between tumors with high and low expression level. This may help to identify breast cancer patients benefiting from HER2-targeting therapies. The best discrimination was at 4h post injection. Due to longer half-life, a positron-emitting radionuclide 44 Sc (T ½ =4.04h) might be a preferable label for Affibody molecules for imaging at several hours after injection., Methods: A synthetic second-generation anti-HER2 Affibody molecule Z HER2:2891 was labeled with 44 Sc via a DOTA-chelator conjugated to the N-terminal amino group. Binding specificity, affinity and cellular processing 44 Sc-DOTA-Z HER2:2891 and 68 Ga-DOTA-Z HER2:2891 were compared in vitro using HER2-expressing cells. Biodistribution and imaging properties of 44 Sc-DOTA-Z HER2:2891 and 68 Ga-DOTA-Z HER2:2891 were evaluated in Balb/c nude mice bearing HER2-expression xenografts., Results: The labeling yield of 98±2% and specific activity of 7.8GBq/μmol were obtained. The conjugate demonstrated specific binding to HER2-expressing SKOV3.ip cells in vitro and to SKOV3.ip xenografts in nude mice. The distribution of radioactivity at 3h post injection was similar for 44 Sc-DOTA-Z HER2:2891 and 68 Ga-DOTA-Z HER2:2891 , but the blood clearance of the 44 Sc-labeled variant was slower and the tumor-to-blood ratio was reduced (15±2 for 44 Sc-DOTA-Z HER2:2891 vs 46±9 for 68 Ga-DOTA-Z HER2:2891 ). At 6h after injection of 44 Sc-DOTA-Z HER2:2891 the tumor uptake was 8±2% IA/g and the tumor-to-blood ratio was 51±8. Imaging using small-animal PET/CT demonstrated that 44 Sc-DOTA-Z HER2:2891 provides specific and high-contrast imaging of HER2-expressing xenografts., Conclusion: The 44 Sc- DOTA-Z HER2:2891 Affibody molecule is a promising probe for imaging of HER2-expression in malignant tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Radiolabelled peptides with high specificity and affinity towards receptors that are overexpressed by tumour cells are used in nuclear medicine for the diagnosis (imaging) and therapy of cancer. In some cases, the sequences of peptides under investigations contain methionine (Met), an amino acid prone to oxidation during radiolabelling procedures. The formation of oxidative side products can affect the purity of the final radiopharmaceutical product and/or impair its specificity and affinity towards the corresponding receptor. The replacement of Met with oxidation resistant amino acid analogues, for example, norleucine (Nle), can provide a solution. While this approach has been applied successfully to different radiolabelled peptides, a Met → Nle switch only preserves the length of the amino acid side chain important for hydrophobic interactions but not its hydrogen-bonding properties. We report here the use of methoxinine (Mox), a non-canonical amino acid that resembles more closely the electronic properties of Met in comparison to Nle. Specifically, we replaced Met 15 by Mox 15 and Nle 15 in the binding sequence of a radiometal-labelled human gastrin derivative [d-Glu 10 ]HG(10-17), named MG11 (d-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH 2 ). A comparison of the physicochemical properties of 177 Lu-DOTA[X 15 ]MG11 (X = Met, Nle, Mox) in vitro (cell internalization/externalization properties, receptor affinity (IC 50 ), blood plasma stability and logD) showed that Mox indeed represents a suitable, oxidation-stable amino acid substitute of Met in radiolabelled peptide conjugates. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd., (Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.)

Current standard-of-care treatment for malignant cancers includes radiotherapy and adjuvant chemotherapy. Here, we report increased MAP kinase-interacting kinase (MNK)-regulated phosphorylation of translation initiation factor 4E (eIF4E) in glioma cells upon temozolomide (TMZ) treatment and in medullary thyroid carcinoma (MTC) cells in response to targeted radionuclide therapy. Depletion of MNK activity by using two MNK inhibitors, CGP57380 or cercosporamide, as well as by MNK1-specific knockdown sensitized glioblastoma (GBM) cells and GBM-derived spheres to TMZ. Furthermore, CGP57380 treatment enhanced response of MTC cells to (177)Lu-labeled gastrin analogue. In order to understand how MNK signaling pathways support glioma survival we analyzed putative MNK substrates by quantitative phosphoproteomics in normal condition and in the presence of TMZ. We identified MNK inhibitor-sensitive phosphorylation sites on eIF4G1, mutations of which either influenced eIF4E phosphorylation or glioma cell response to TMZ, pointing to altered regulation of translation initiation as a resistance mechanism. Pharmacological inhibition of overexpressed MNK1 by CGP57380 reduced eIF4E phosphorylation and induced association of inactive MNK1 with eIF4G1. Taken together, our data show an activation of MNK-mediated survival mechanisms in response to either glioma chemotherapy or MTC targeted radiation and suggest that inhibition of MNK activity represents an attractive sensitizing strategy for cancer treatments., (Copyright © 2016 Elsevier Inc. All rights reserved.)

PET is the favored nuclear imaging technique because of the high sensitivity and resolution it provides, as well as the possibility for quantification of accumulated radioactivity. (44)Sc (T1/2=3.97h, Eβ(+)=632keV) was recently proposed as a potentially interesting radionuclide for PET. The aim of this study was to investigate the image quality, which can be obtained with (44)Sc, and compare it with five other, frequently employed PET nuclides using Derenzo phantoms and a small-animal PET scanner. The radionuclides were produced at the medical cyclotron at CRS, ETH Zurich ((11)C, (18)F), at the Injector II research cyclotron at CRS, PSI ((64)Cu, (89)Zr, (44)Sc), as well as via a generator system ((68)Ga). Derenzo phantoms, containing solutions of each of these radionuclides, were scanned using a GE Healthcare eXplore VISTA small-animal PET scanner. The image resolution was determined for each nuclide by analysis of the intensity signal using the reconstructed PET data of a hole diameter of 1.3mm. The image quality of (44)Sc was compared to five frequently-used PET radionuclides. In agreement with the positron range, an increasing relative resolution was determined in the sequence of (68)Ga<(44)Sc<(89)Zr<(11)C<(64)Cu<(18)F. The performance of (44)Sc was in agreement with the theoretical expectations based on the energy of the emitted positrons., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with (67)Cu- and (177)Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide (177)Lu and the potential alternative (161)Tb in an ovarian cancer therapy model., Methods: Tb was produced by neutron bombardment of enriched (160)Gd targets. (161)Tb and (177)Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of (177)Lu- and (161)Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours., Results: The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. (177)Lu- and (161)Tb-DOTA-chCE7 showed high tumour uptake (37.8-39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. (161)Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the (177)Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the (161)Tb-DOTA-chCE7 than the (177)Lu-DOTA-chCE7 RIT., Conclusions: Our study is the first to show that anti-L1CAM (161)Tb RIT is more effective compared to (177)Lu RIT in ovarian cancer xenografts. These results suggest that (161)Tb is a promising candidate for future clinical applications in combination with internalising antibodies.

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: In recent years, implementation of (68)Ga-radiometalated peptides for PET imaging of cancer has attracted the attention of clinicians. Herein, we propose the use of (44)Sc (half-life = 3.97 h, average β(+) energy [Eβ(+)av] = 632 keV) as a valuable alternative to (68)Ga (half-life = 68 min, Eβ(+)av = 830 keV) for imaging and dosimetry before (177)Lu-based radionuclide therapy. The aim of the study was the preclinical evaluation of a folate conjugate labeled with cyclotron-produced (44)Sc and its in vitro and in vivo comparison with the (177)Lu-labeled pendant., Methods: (44)Sc was produced via the (44)Ca(p,n)(44)Sc nuclear reaction at a cyclotron (17.6 ± 1.8 MeV, 50 μA, 30 min) using an enriched (44)Ca target (10 mg (44)CaCO3, 97.00%). Separation from the target material was performed by a semiautomated process using extraction chromatography and cation exchange chromatography. Radiolabeling of a DOTA-folate conjugate (cm09) was performed at 95°C within 10 min. The stability of (44)Sc-cm09 was tested in human plasma. (44)Sc-cm09 was investigated in vitro using folate receptor-positive KB tumor cells and in vivo by PET/CT imaging of tumor-bearing mice, Results: Under the given irradiation conditions, (44)Sc was obtained in a maximum yield of 350 MBq at high radionuclide purity (>99%). Semiautomated isolation of (44)Sc from (44)Ca targets allowed formulation of up to 300 MBq of (44)Sc in a volume of 200-400 μL of ammonium acetate/HCl solution (1 M, pH 3.5-4.0) within 10 min. Radiolabeling of cm09 was achieved with a radiochemical yield of greater than 96% at a specific activity of 5.2 MBq/nmol. In vitro, (44)Sc-cm09 was stable in human plasma over the whole time of investigation and showed folate receptor-specific binding to KB tumor cells. PET/CT images of mice injected with (44)Sc-cm09 allowed excellent visualization of tumor xenografts. Comparison of cm09 labeled with (44)Sc and (177)Lu revealed almost identical pharmacokinetics., Conclusion: This study presents a high-yield production and efficient separation method of (44)Sc at a quality suitable for radiolabeling of DOTA-functionalized biomolecules. An in vivo proof-of-concept study using a DOTA-folate conjugate demonstrated the excellent features of (44)Sc for PET imaging. Thus, (44)Sc is a valid alternative to (68)Ga for imaging and dosimetry before (177)Lu-radionuclide tumor therapy.

Unlabelled: The folate receptor (FR) has proven a valuable target for nuclear imaging using folic acid radioconjugates. However, using folate-based radiopharmaceuticals for therapy has long been regarded as an unattainable goal because of their considerable renal accumulation. Herein, we present a novel strategy in which a DOTA-folate conjugate with an albumin-binding entity (cm09) was designed with the aim of prolonging circulation in the blood and therewith potentially improving tumor-to-kidney ratios., Methods: The folate conjugate cm09 was radiolabeled with (177)LuCl(3), and stability experiments were performed in plasma. Cell uptake studies were performed on FR-positive KB tumor cells, and an ultrafiltration assay was used to determine the plasma protein-binding properties of (177)Lu-cm09. In vivo, (177)Lu-cm09 was tested in KB tumor-bearing mice using SPECT/CT. The therapeutic anticancer effect of (177)Lu-cm09 (20 MBq) applied as a single injection or as fractionated injections was investigated in different groups of mice (n = 5) by monitoring tumor size and the survival time of treated mice, compared with untreated controls., Results: Compound cm09 was radiolabeled at a specific activity of 40 MBq/nmol, a radiochemical yield of more than 98%, and a stability of more than 99% over 5 d in plasma. Ultrafiltration revealed significant binding of (177)Lu-cm09 to serum proteins (∼91%) in plasma, compared with folate radioconjugate without an albumin-binding entity. Cell uptake and internalization of (177)Lu-cm09 was FR-specific and comparable to other folate radioconjugates. In vivo studies resulted in high tumor uptake (17.56 percentage injected dose per gram [%ID/g] at 4 h after injection), which was almost completely retained for at least 72 h. Renal accumulation was significantly reduced (28 %ID/g at 4 h after injection), compared with folate conjugates that lack an albumin-binding entity (∼70 %ID/g at 4 h after injection). These circumstances enabled SPECT imaging of excellent quality. Radionuclide therapy (1 × 20 MBq) revealed complete remission of tumors in 4 of 5 cases and a significantly prolonged survival time, compared with untreated controls., Conclusion: The modification of a folate radioconjugate with an albumin-binding entity resulted in a significant increase of the tumor-to-kidney ratio of radioactivity, enabling for the first time, to our knowledge, the preclinical application of folic acid-targeted radionuclide therapy in mice.

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.

Introduction: The low-energy β(-) emitter (161)Tb is very similar to (177)Lu with respect to half-life, beta energy and chemical properties. However, (161)Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to (177)Lu. It also emits low-energy photons that are useful for gamma camera imaging., Methods: The (160)Gd(n,γ)(161)Gd→(161)Tb production route was used to produce (161)Tb by neutron irradiation of massive (160)Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) (161)Tb from the bulk of the (160)Gd target and from its stable decay product (161)Dy. (161)Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. (177)Lu. A (161)Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera., Results: Up to 15 GBq of (161)Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%-90% of the available (161)Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The (161)Tb obtained was of the quality required to prepare (161)Tb-DOTA-Tyr3-octreotate., Conclusions: We were able to produce (161)Tb in n.c.a. form by irradiating highly enriched (160)Gd targets; it can be obtained in the quantity and quality required for the preparation of (161)Tb-labeled therapeutic agents., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: The most successful clinical studies of immunotherapy in patients with non-Hodgkin's lymphoma (NHL) use the antibody rituximab (RTX) targeting CD20(+) B-cell tumors. Rituximab radiolabeled with β(-) emitters could potentiate the therapeutic efficacy of the antibody by virtue of the particle radiation. Here, we report on a direct radiolabeling approach of rituximab with the (99m)Tc- and (188)Re-tricarbonyl core (IsoLink technology)., Methods: The native format of the antibody (RTX(wt)) as well as a reduced form (RTX(red)) was labeled with (99m)Tc/(188)Re(CO)(3). The partial reduction of the disulfide bonds to produce free sulfhydryl groups (-SH) was achieved with 2-mercaptoethanol. Radiolabeling efficiency, in vitro human plasma stability as well as transchelation toward cysteine and histidine was investigated. The immunoreactivity and binding affinity were determined on Ramos and/or Raji cells expressing CD20. Biodistribution was performed in mice bearing subcutaneous Ramos lymphoma xenografts., Results: The radiolabeling efficiency and kinetics of RTX(red) were superior to that of RTX(wt) ((99m)Tc: 98% after 3 h for RTX(red) vs. 70% after 24 h for RTX(wt)). (99m)Tc(CO)(3)-RTX(red) was used without purification for in vitro and in vivo studies whereas (188)Re(CO)(3)-RTX(red) was purified to eliminate free (188)Re-precursor. Both radioimmunoconjugates were stable in human plasma for 24 h at 37 °C. In contrast, displacement experiments with excess cysteine/histidine showed significant transchelation in the case of (99m)Tc(CO)(3)-RTX(red) but not with pre-purified (188)Re(CO)(3)-RTX(red). Both conjugates revealed high binding affinity to the CD20 antigen (K(d) = 5-6 nM). Tumor uptake of (188)Re(CO)(3)-RTX(red) was 2.5 %ID/g and 0.8 %ID/g for (99m)Tc(CO)(3)-RTX(red) 48 h after injection. The values for other organs and tissues were similar for both compounds, for example the tumor-to-blood and tumor-to-liver ratios were 0.4 and 0.3 for (99m)Tc(CO)(3)-RTX(red) and for (188)Re(CO)(3)-RTX(red) 0.5 and 0.5 (24 h pi)., Conclusion: Rituximab could be directly and stably labeled with the matched pair (99m)Tc/(188)Re using the IsoLink technology under retention of the biological activity. Labeling kinetics and yields need further improvement for potential routine application in radioimmunodiagnosis and therapy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Simple Summary: Delivering high radiation dose to a tumor is a crucial prerequisite for therapeutic radiopharmaceuticals. It was previously shown that folate radioconjugates profit from modification with an albumin-binding moiety, which results in increased tumor uptake and reduced retention in the kidneys. In this study, the impact of the type of albumin binder and adjacent linker entity was systematically investigated. It was revealed that 4-(p-iodophenyl)butanoate binds to albumin with higher affinity than 5-(p-iodophenyl)pentanoate, and the presence of an adjacent hydrophobic 4-(aminomethyl)benzoic acid (AMBA) linker increased the binding in both cases even further. Stronger albumin-binding properties translated into enhanced blood residence of the respective folate radioconjugates, while the blood circulation time was found to be inversely linked to the radioconjugates' renal accumulation. This study demonstrated that subtle changes in the albumin-binding entity and the adjacent linker unit can serve for fine-tuning the radioconjugates' tissue distribution profiles to find an optimum tumor uptake and a balance between retention in the blood and kidneys. Introducing an albumin-binding entity into otherwise short-lived radiopharmaceuticals can be an effective means to improve their pharmacokinetic properties due to enhanced blood residence time. In the current study, DOTA-derivatized albumin binders based on 4-(p-iodophenyl)butanoate (DOTA-ALB-1 and DOTA-ALB-3) and 5-(p-iodophenyl)pentanoate entities (DOTA-ALB-24 and DOTA-ALB-25) without and with a hydrophobic 4-(aminomethyl)benzoic acid (AMBA) linker unit, respectively, were synthesized and labeled with lutetium-177 for in vitro and in vivo comparison. Overall, [177Lu]Lu-DOTA-ALB-1 demonstrated ~3-fold stronger in vitro albumin-binding affinity and a longer blood residence time (T50%IA ~8 h) than [177Lu]Lu-DOTA-ALB-24 (T50%IA ~0.8 h). Introducing an AMBA linker enhanced the albumin-binding affinity, resulting in a T50%IA of ~24 h for [177Lu]Lu-DOTA-ALB-3 and ~2 h for [177Lu]Lu-DOTA-ALB-25. The same albumin binders without or with the AMBA linker were incorporated into 6R- and 6S-5-methyltetrahydrofolate-based DOTA-conjugates (177Lu-RedFols). Biodistribution studies in mice performed with both diastereoisomers of [177Lu]Lu-RedFol-1 and [177Lu]Lu-RedFol-3, which comprised the 4-(p-iodophenyl)butanoate moiety, demonstrated a slower accumulation in KB tumors than those of [177Lu]Lu-RedFol-24 and [177Lu]Lu-RedFol-25 with the 5-(p-iodophenyl)pentanoate entity. In all cases, the tumor uptake was high (30–45% IA/g) 24 h after injection. Both diastereoisomers of [177Lu]Lu-RedFol-1 and [177Lu]Lu-RedFol-3 demonstrated high blood retention (3.8–8.7% IA/g, 24 h p.i.) and a 2- to 4-fold lower kidney uptake than the corresponding diastereoisomers of [177Lu]Lu-RedFol-24 and [177Lu]Lu-RedFol-25, which were more rapidly cleared from the blood (<0.2% IA/g, 24 h after injection). Kidney retention of the 6S-diastereoisomers of all 177Lu-RedFols was consistently higher than that of the respective 6R-diastereoisomers, irrespective of the albumin binder and linker unit used. It was demonstrated that the blood clearance data obtained with 177Lu-DOTA-ALBs had predictive value for the blood retention times of the respective folate radioconjugates. The use of these albumin-binding entities without or with an AMBA linker may serve for fine-tuning the blood retention of folate radioconjugates and also other radiopharmaceuticals and, hence, optimize their tissue distribution profiles. Dosimetry estimations based on patient data obtained with one of the most promising folate radioconjugates will be crucial to identify the dose-limiting organ, which will allow for selecting the most suitable folate radioconjugate for therapeutic purposes. [ABSTRACT FROM AUTHOR]

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]

Purpose: The folate receptor (FR) is frequently overexpressed in a variety of tumor types and, hence, an interesting target for radionuclide therapy. The aim of this study was to evaluate a new class of albumin-binding radioconjugates comprising 5-methyltetrahydrofolate (5-MTHF) as a targeting agent and to compare their properties with those of the previously established folic acid-based [177Lu]Lu-OxFol-1. Methods: [177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-6S-RedFol-1 were investigated in vitro using FR-positive KB tumor cells. Biodistribution studies were performed in KB tumor-bearing mice, and the areas under the curve (AUC0 → 120h) were determined for the uptake in tumors and kidneys. [177Lu]Lu-6R-RedFol-1 was compared with [177Lu]Lu-OxFol-1 in a therapy study over 8 weeks using KB tumor-bearing mice. Results: Both radioconjugates demonstrated similar in vitro properties as [177Lu]Lu-OxFol-1; however, the tumor uptake of [177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-6S-RedFol-1 was significantly increased in comparison with [177Lu]Lu-OxFol-1. In the case of [177Lu]Lu-6S-RedFol-1, also the kidney uptake was increased; however, renal retention of [177Lu]Lu-6R-RedFol-1 was similar to that of [177Lu]Lu-OxFol-1. This led to an almost 4-fold increased tumor-to-kidney AUC0 → 120h ratio of [177Lu]Lu-6R-RedFol-1 as compared with [177Lu]Lu-6S-RedFol-1 and [177Lu]Lu-OxFol-1. At equal activity, the therapeutic effect of [177Lu]Lu-6R-RedFol-1 was better than that of [177Lu]Lu-OxFol-1, reflected by a slower tumor growth and, consequently, an increased median survival time (49 days vs. 34 days). Conclusion: This study demonstrated the promising potential of 5-MTHF-based radioconjugates for FR-targeting. Application of [177Lu]Lu-6R-RedFol-1 resulted in unprecedentedly high tumor-to-kidney ratios and, as a consequence, a superior therapeutic effect as compared with [177Lu]Lu-OxFol-1. These findings, together with the absence of early side effects, make [177Lu]Lu-6R-RedFol-1 attractive in view of a future clinical translation. [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]

Folate-based radiopharmaceuticals have the potential to be used for imaging and therapy of tumours positive for the folate receptor (FR). We describe the in vitro and in vivo evaluation of a DOTA–folate conjugate. Radiolabelling of the DOTA-folate was carried out via standard procedures using 111InCl3 and 177LuCl3, respectively. The distribution coefficient (log D) was determined in octanol/PBS (pH 7.4). Tissue distribution was investigated in nude mice bearing KB tumour xenografts at different time points after administration of 111In-DOTA-folate (radiofolate 1) or 177Lu-DOTA-folate (radiofolate 2) (1 MBq, 1 nmol per mouse). Pemetrexed (PMX, 400 μg) was injected 1 h prior to the radiofolate in order to reduce renal uptake. Images were acquired with a SPECT/CT camera 24 h after injection of the radiofolate (40–50 MBq, 3 nmol per mouse). The hydrophilic character of the DOTA-folate was represented by a low log D value ( radiofolate 1 −4.21±0.11). In vivo, maximal tumour uptake was found 4 h after injection ( radiofolate 1 5.80±0.55% ID/g; radiofolate 2 7.51±1.25% ID/g). In FR-positive kidneys there was considerable accumulation of the radiofolates ( radiofolate 1 55.88±3.91% ID/g; radiofolate 2 57.22±11.05% ID/g; 4 h after injection). However, renal uptake was reduced by preinjection of PMX ( radiofolate 1 9.52±1.07% ID/g; radiofolate 2 13.43±0.54% ID/g; 4 h after injection) whereas the tumour uptake was retained ( radiofolate 1 6.32±0.41% ID/g; radiofolate 2 8.99±0.43% ID/g; 4 h after injection). SPECT/CT images clearly confirmed favourable tissue distribution of the novel radiofolates and the positive effect of PMX. The preliminary requirements for the therapeutic use of the novel DOTA-folate are met by its favourable tissue distribution that can be ascribed to its hydrophilic properties and combined administration with PMX. [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]

Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused radiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic radiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was aimed to perform an initial dose-searching study for the combination of these treatment modalities in a preclinical setting. Therapy studies were performed with xenograft mouse models of folate receptor (FR)-positive KB and prostate-specific membrane antigen (PSMA)-positive PC-3 PIP tumors, respectively. PT and TRT using 177Lu-folate and 177Lu-PSMA-617, respectively, were applied either as single treatments or in combination. Monitoring of the mice over nine weeks revealed a similar tumor growth delay after PT and TRT, respectively, when equal tumor doses were delivered either by protons or by β¯-particles, respectively. Combining the methodologies to provide half-dose by either therapy approach resulted in equal (PC-3 PIP tumor model) or even slightly better therapy outcomes (KB tumor model). In separate experiments, preclinical positron emission tomography (PET) was performed to investigate tissue activation after proton irradiation of the tumor. The high-precision radiation delivery of PT was confirmed by the resulting PET images that accurately visualized the irradiated tumor tissue. In this study, the combination of PT and TRT resulted in an additive effect or a trend of synergistic effects, depending on the type of tumor xenograft. This study laid the foundation for future research regarding therapy options in the situation of metastasized solid tumors, where surgery or PT alone are not a solution but may profit from combination with systemic radiation therapy. [ABSTRACT FROM AUTHOR]

Targeted radionuclide therapy with 177Lu- and 90Y-labeled radioconjugates is a clinically-established treatment modality for metastasized cancer. 47Sc is a therapeutic radionuclide that decays with a half-life of 3.35 days and emits medium-energy β−-particles. In this study, 47Sc was investigated, in combination with a DOTA-folate conjugate, and compared to the therapeutic properties of 177Lu-folate and 90Y-folate, respectively. In vitro, 47Sc-folate demonstrated effective reduction of folate receptor-positive ovarian tumor cell viability similar to 177Lu-folate, but 90Y-folate was more potent at equal activities due to the higher energy of emitted β−-particles. Comparable tumor growth inhibition was observed in mice that obtained the same estimated absorbed tumor dose (~21 Gy) when treated with 47Sc-folate (12.5 MBq), 177Lu-folate (10 MBq), and 90Y-folate (5 MBq), respectively. The treatment resulted in increased median survival of 39, 43, and 41 days, respectively, as compared to 26 days in untreated controls. There were no statistically significant differences among the therapeutic effects observed in treated groups. Histological assessment revealed no severe side effects two weeks after application of the radiofolates, even at double the activity used for therapy. Based on the decay properties and our results, 47Sc is likely to be comparable to 177Lu when employed for targeted radionuclide therapy. It may, therefore, have potential for clinical translation and be of particular interest in tandem with 44Sc or 43Sc as a diagnostic match, enabling the realization of radiotheragnostics in future. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]