Simultaneous Visualization of 161Tb- and 177Lu-Labeled Somatostatin Analogues Using Dual-Isotope SPECT Imaging

Borgna, Francesca; Barritt, Patrick; Grundler, Pascal V.; Talip, Zeynep; Cohrs, Susan; Zeevaart, Jan Rijn; Köster, U.; Schibli, Roger; Meulen, Nicholas P. van der; Müller, Cristina

doi:10.3390/pharmaceutics13040536

Cited by 28 publications

(35 citation statements)

References 41 publications

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“…Tumor cell uptake and localization DOTA-LM3, irrespective of whether it was labeled with terbium-161 or lutetium-177 [43], showed the highest AR42J tumor cell uptake in vitro with ~70% of total added activity after a 2-h incubation period. This was 4-to sixfold higher than the uptake of radiolabeled DOTATOC (~ 10%) and DOTATOC-NLS (~ 15%), respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Since it was previously confirmed that the SST analogues have equal in vitro and in vivo behavior regarding (sub)cellular uptake and tissue distribution, irrespective of whether they were labeled with lutetium-177 or terbium-161 [43], those experiments were performed with only one version of the radiolabeled peptides.…”

Section: Methodsmentioning

confidence: 99%

“…lutetium-177 was obtained from ITM Medical Isotopes GmbH, Germany. Radiolabeling and quality control of the SST analogues were performed as previously reported [43].…”

Section: Radiopeptide Preparationmentioning

confidence: 99%

“…AR42J tumor cells, a SSTR-positive exocrine rat pancreatic cancer cell line [44] (ECACC 93,100,618, Health Protection Agency Culture Collections, Salisbury, UK), were cultured as previously reported (Supplementary Material) [43]. Cell uptake and internalization studies were performed to determine the fractions of radiopeptides localized at the membrane or in the cytoplasm, respectively.…”

Section: Ar42j Tumor Cell Uptake and Internalizationmentioning

confidence: 99%

“…The studies were performed 10-14 days after tumor cell inoculation when the tumor size reached a volume of ~ 250 mm 3 . [ 161 Tb]Tb-DOTATOC, [ 161 Tb]Tb-DOTATOC-NLS, or [ 161 Tb]Tb-DOTA-LM3 (15 MBq, 1 nmol) was injected to acquire scans under isoflurane/oxygen anesthesia using a dedicated small-animal SPECT/CT scanner (NanoSPECT/CT, Mediso Medical Imaging Systems, Budapest, Hungary) as previously reported (Supplementary Material) [43]. In a first series of biodistribution studies, it was subsequently assessed that a molar peptide amount of 0.2 nmol per mouse was the optimum to achieve high tumorto-background ratios (Supplementary Material).…”

Section: Spect/ct Imaging and Biodistribution Studiesmentioning

confidence: 99%

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Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Borgna

Haller

Rodríguez

et al. 2021

Eur J Nucl Med Mol Imaging

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…lutetium-177 was obtained from ITM Medical Isotopes GmbH, Germany. Radiolabeling and quality control of the SST analogues were performed as previously reported [43].…”

Section: Radiopeptide Preparationmentioning

confidence: 99%

Section: Ar42j Tumor Cell Uptake and Internalizationmentioning

confidence: 99%

Section: Spect/ct Imaging and Biodistribution Studiesmentioning

confidence: 99%

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Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Borgna

Haller

Rodríguez

et al. 2021

Eur J Nucl Med Mol Imaging

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Opportunities and potential challenges of using terbium-161 for targeted radionuclide therapy in clinics

Müller

Meulen

Schibli

2023

Eur J Nucl Med Mol Imaging

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Comparison of the tolerability of 161Tb- and 177Lu-labeled somatostatin analogues in the preclinical setting

Busslinger,

Mapanao,

Kegler

et al. 2024

Eur J Nucl Med Mol Imaging

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Purpose [177Lu]Lu-DOTATATE is an established somatostatin receptor (SSTR) agonist for the treatment of metastasized neuroendocrine neoplasms, while the SSTR antagonist [177Lu]Lu-DOTA-LM3 has only scarcely been employed in clinics. Impressive preclinical data obtained with [161Tb]Tb-DOTA-LM3 in tumor-bearing mice indicated the potential of terbium-161 as an alternative to lutetium-177. The aim of the present study was to compare the tolerability of 161Tb- and 177Lu-based DOTA-LM3 and DOTATATE in immunocompetent mice. Methods Dosimetry calculations were performed based on biodistribution data of the radiopeptides in immunocompetent mice. Treatment-related effects on blood cell counts were assessed on Days 10, 28 and 56 after application of [161Tb]Tb-DOTA-LM3 or [161Tb]Tb-DOTATATE at 20 MBq per mouse. These radiopeptides were also applied at 100 MBq per mouse and the effects compared to those observed after application of the 177Lu-labeled counterparts. Bone marrow smears, blood plasma parameters and organ histology were assessed at the end of the study. Results The absorbed organ dose was commonly higher for the SSTR antagonist than for the SSTR agonist and for terbium-161 over lutetium-177. Application of a therapeutic activity level of 20 MBq [161Tb]Tb-DOTA-LM3 or [161Tb]Tb-DOTATATE was well tolerated without major hematological changes. The injection of 100 MBq of the 161Tb- and 177Lu-based somatostatin analogues affected the blood cell counts, however. The lymphocytes were 40–50% lower in treated mice compared to the untreated controls on Day 10 irrespective of the radionuclide employed. At the same timepoint, thrombocyte and erythrocyte counts were 30–50% and 6–12% lower, respectively, after administration of the SSTR antagonist (p < 0.05) while changes were less pronounced in mice injected with the SSTR agonist. All blood cell counts were in the normal range on Day 56. Histological analyses revealed minimal abnormalities in the kidneys, liver and spleen of treated mice. No correlation was observed between the organ dose and frequency of the occurrence of abnormalities. Conclusion Hematologic changes were more pronounced in mice treated with the SSTR antagonist than in those treated with the SSTR agonist. Despite the increased absorbed dose delivered by terbium-161 over lutetium-177, [161Tb]Tb-DOTA-LM3 and [161Tb]Tb-DOTATATE should be safe at activity levels that are recommended for their respective 177Lu-based analogues. Graphical Abstract

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Simultaneous Visualization of 161Tb- and 177Lu-Labeled Somatostatin Analogues Using Dual-Isotope SPECT Imaging

Cited by 28 publications

References 41 publications

Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Opportunities and potential challenges of using terbium-161 for targeted radionuclide therapy in clinics

Comparison of the tolerability of 161Tb- and 177Lu-labeled somatostatin analogues in the preclinical setting

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