Top

Published in:

Open Access 01-12-2016 | Original research

¹⁷⁷Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model

Authors: Seval Beykan, Jan S. Dam, Uta Eberlein, Jens Kaufmann, Benedict Kjærgaard, Lars Jødal, Hakim Bouterfa, Romain Bejot, Michael Lassmann, Svend Borup Jensen

Published in: EJNMMI Research | Issue 1/2016

Abstract

Background

¹⁷⁷Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of ¹⁷⁷Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications.

Results

¹⁷⁷Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 % in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 % of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq ¹⁷⁷Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of ¹⁷⁷Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels.

Conclusions

The ¹⁷⁷Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.

Available only for authorised users

In the literature, often also called “DOTA-JR11”.

In the literature, often also called “NODAGA-JR11”.

Meredith RF, Partridge EE, Alvarez RD, Khazaeli MB, Plott G, Russell CD, et al. Intraperitoneal radioimmunotherapy of ovarian cancer with lutetium-177-CC49. J Nucl Med. 1996;37:1491–6.PubMed

Lassmann M, Eberlein U. Radiation dosimetry aspects of (177)Lu. Curr Radiopharm. 2015;8:139–44.CrossRefPubMed

Bodei L, Cremonesi M, Grana CM, Fazio N, Iodice S, Baio SM, et al. Peptide receptor radionuclide therapy with (1)(7)(7)Lu-DOTATATE: the IEO phase I–II study. Eur J Nucl Med Mol Imaging. 2011;38:2125–35.CrossRefPubMed

Sandstrom M, Garske-Roman U, Granberg D, Johansson S, Widstrom C, Eriksson B, et al. Individualized dosimetry of kidney and bone marrow in patients undergoing ¹⁷⁷Lu-DOTA-octreotate treatment. J Nucl Med. 2013;54:33–41.CrossRefPubMed

Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Horsch D, O'Dorisio MS, et al. The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nuc Med Mod Imaging. 2013;40:800-16.

Mariniello A, Bodei L, Tinelli C, Baio SM, Gilardi L, Colandrea M, et al. Long-term results of PRRT in advanced bronchopulmonary carcinoid. Eur J Nucl Med Mol Imaging. 2016;43:441–52.CrossRefPubMed

van Essen M, Krenning EP, Kam BL, de Jong M, Valkema R, Kwekkeboom DJ. Peptide-receptor radionuclide therapy for endocrine tumors. Nat Rev Endocrinol. 2009;5:382–93.CrossRefPubMed

Bombardieri E, Ambrosini V, Aktolun C, Baum RP, Bishof-Delaloye A, Del Vecchio S, et al. ¹¹¹In-pentetreotide scintigraphy: procedure guidelines for tumour imaging. Eur J Nucl Med Mol Imaging. 2010;37:1441–8.CrossRefPubMed

Bodei L, Kidd M, Paganelli G, Grana CM, Drozdov I, Cremonesi M, et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur J Nucl Med Mol Imaging. 2015;42:5–19.CrossRefPubMed

10.

Wild D, Fani M, Fischer R, Del Pozzo L, Kaul F, Krebs S, et al. Comparison of somatostatin receptor agonist and antagonist for peptide receptor radionuclide therapy: a pilot study. J Nucl Med. 2014;55:1248–52.CrossRefPubMed

11.

Wild D, Fani M, Behe M, Brink I, Rivier JE, Reubi JC, et al. First clinical evidence that imaging with somatostatin receptor antagonists is feasible. J Nucl Med. 2011;52:1412–7.CrossRefPubMed

12.

Dalm SU, Nonnekens J, Doeswijk GN, de Blois E, van Gent DC, Konijnenberg MW, et al. Comparison of the therapeutic response to treatment with a 177-lutetium labeled somatostatin receptor agonist and antagonist in preclinical models. J Nucl Med. 2016;57:260-5

13.

Cescato R, Waser B, Fani M, Reubi JC. Evaluation of 177Lu-DOTA-sst2 antagonist versus 177Lu-DOTA-sst2 agonist binding in human cancers in vitro. J Nucl Med. 2011;52:1886–90.CrossRefPubMed

14.

Ginj M, Zhang H, Waser B, Cescato R, Wild D, Wang X, et al. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci U S A. 2006;103:16436–41.CrossRefPubMedPubMedCentral

15.

Shen S, Meredith RF, Duan J, Macey DJ, Khazaeli MB, Robert F, et al. Improved prediction of myelotoxicity using a patient-specific imaging dose estimate for non-marrow-targeting (90)Y-antibody therapy. J Nucl Med. 2002;43:1245–53.PubMed

16.

Kletting P, Schimmel S, Kestler HA, Hanscheid H, Luster M, Fernandez M, et al. Molecular radiotherapy: the NUKFIT software for calculating the time-integrated activity coefficient. Med Phys. 2013;40:102504.CrossRefPubMed

17.

Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 2005;46:1023–7.PubMed

18.

Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21:109–22.CrossRefPubMed

19.

First clinical data on Ga-68-labeled somatostatin receptor antagonists: a phase I/II study comparing Ga-68-OPS202 with Ga-68-DOTATOC PET/CT. J Nucl Med. 2015;56(S3):266.

20.

Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22:659–61.CrossRefPubMed

21.

Sparks RB AB. Comparison of the effectiveness of some common animal data scaling techniques in estimating human radiation dose. Sixth International Radiopharmaceutical Dosimetry Symposium. 1999;705–16

22.

Repetto-Llamazares AH, Larsen RH, Mollatt C, Lassmann M, Dahle J. Biodistribution and dosimetry of (177)Lu-tetulomab, a new radioimmunoconjugate for treatment of non-Hodgkin lymphoma. Curr Radiopharm. 2013;6:20–7.CrossRefPubMedPubMedCentral

Title: 177Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model
Authors: Seval Beykan
Jan S. Dam
Uta Eberlein
Jens Kaufmann
Benedict Kjærgaard
Lars Jødal
Hakim Bouterfa
Romain Bejot
Michael Lassmann
Svend Borup Jensen
Publication date: 01-12-2016
Publisher: Springer Berlin Heidelberg
Published in: EJNMMI Research / Issue 1/2016
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-016-0204-9

At a glance: The STEP trials

Springer Medicine

¹⁷⁷Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model

Abstract

Background

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

82Rb PET imaging of myocardial blood flow—have we achieved the 4 “R”s to support routine use?

The effect of isoflurane on 18F-FDG uptake in the rat brain: a fully conscious dynamic PET study using motion compensation

A new method to quantify tau pathologies with 11C-PBB3 PET using reference tissue voxels extracted from brain cortical gray matter

Pharmacokinetic modeling of [18F]fluorodeoxyglucose (FDG) for premature infants, and newborns through 5-year-olds

Fluorescence imaging of in vivo miR-124a-induced neurogenesis of neuronal progenitor cells using neuron-specific reporters

Targeting of radiolabeled J591 antibody to PSMA-expressing tumors: optimization of imaging and therapy based on non-linear compartmental modeling