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Current Radiopharmaceuticals


ISSN (Print): 1874-4710
ISSN (Online): 1874-4729

Research Article

Dosimetry and Toxicity Studies of the Novel Sulfonamide Derivative of Sulforhodamine 101([18F]SRF101) at a Preclinical Level

Author(s): Ingrid Kreimerman, Erick Mora-Ramirez, Laura Reyes, Manuel Bardiès, Eduardo Savio* and Henry Engler

Volume 12, Issue 1, 2019

Page: [40 - 48] Pages: 9

DOI: 10.2174/1874471011666180830145304

open access plus


Background: The SR101 N-(3-[18F]Fluoropropyl) sulfonamide ([18F]SRF101) is a Sulforhodamine 101 derivative that was previously synthesised by our group. The fluorescent dye SR101 has been reported as a marker of astroglia in the neocortex of rodents in vivo.

Objective: The aim of this study was to perform a toxicological evaluation of [18F]SRF101 and to estimate human radiation dosimetry based on preclinical studies.

Methods: Radiation dosimetry studies were conducted based on biokinetic data obtained from a mouse model. A single-dose toxicity study was carried out. The toxicological limit chosen was <100 μg, and allometric scaling with a safety factor of 100 for unlabelled SRF101 was selected.

Results: The absorbed and effective dose estimated using OLINDA/EXM V2.0 for male and female dosimetric models presented the same tendency. The highest total absorbed dose values were for different sections of the intestines. The mean effective dose was 4.03 x10-3 mSv/MBq and 5.08 x10-3 mSv/MBq for the male and female dosimetric models, respectively, using tissue-weighting factors from ICRP-89.

The toxicity study detected no changes in the organ or whole-body weight, food consumption, haematologic or clinical chemistry parameters. Moreover, lesions or abnormalities were not found during the histopathological examination.

Conclusion: The toxicological evaluation of SRF101 verified the biosafety of the radiotracer for human administration. The dosimetry calculations revealed that the radiation-associated risk of [18F]SRF101 would be of the same order as other 18F radiopharmaceuticals used in clinical applications. These study findings confirm that the novel radiotracer would be safe for use in human PET imaging.

Keywords: Preclinical evaluation, toxicity, dosimetry, [18F]SRF101, PET radiotracers, tissue-weighting factors.

Graphical Abstract
Kreimerman, I.; Porcal, W.; Oliver, P.; Savio, E.; Engler, H. Synthesis of [18F] 2B-SRF101: A sulfonamide derivative of the fluorescent dye sulforhodamine 101. Curr. Radiopharm., 2017, 10(3), 212-220.
Nimmerjahn, A.; Kirchhoff, F.; Kerr, J.N.D.; Helmchen, F. Sulforhodamine 101 as a Specific Marker of Astroglia in the Neocortex in vivo. Nat. Methods, 2004, 1(1), 31-37.
Nimmerjahn, A. Helmchen vivo labeling of cortical astrocytes with sulforhodamine 101 (SR101). Cold Spring Harb. Protoc., 2012, 7(3), 326-334.
Wasseff, S.K.; Scherer, S.S. Cx32 and Cx47 mediate oligodendrocyte: astrocyte and oligodendrocyte: Oligodendrocyte gap junction coupling. Neurobiol. Dis., 2011, 42(3), 506-513.
Hill, R.A.; Grutzendler, J. In vivo Imaging of Oligodendrocytes with Sulforhodamine 101. Nat. Methods, 2014, 11(11), 1081-1082.
Hagos, L.; Hülsmann, S. Unspecific labelling of oligodendrocytes by sulforhodamine 101 depends on astrocytic uptake via the thyroid hormone transporter OATP1C1 (SLCO1C1). Neurosci. Lett., 2016, 631, 13-18.
Hülsmann, S.; Hagos, L.; Heuer, H.; Schnell, C. Limitations of sulforhodamine 101 for brain imaging. Front. Cell. Neurosci., 2017, 11, 1-6.
Verkhratsky, A.; Olabarria, M.; Noristani, H.N.; Yeh, C.Y.; Rodriguez, J.J. Astrocytes in alzheimer’s disease. Neurotherapeutics, 2010, 7(4), 399-412.
Kreimerman, I.; Reyes, A.L.; Buccino, P.; Porcal, W.; Oliver, P.; Savio, E.; Engler, H. 18F-Sulforhodamine 101 derivative as a potential agent for astrocytosis diagnosis: Labelling and preliminary biological studies. J. Nucl. Med., 2016, 5(2), 2701a.
Kranz, M.; Sattler, B.; Tiepolt, S.; Wilke, S.; Deuther-Conrad, W.; Donat, C.K.; Fischer, S.; Patt, M.; Schildan, A.; Patt, J.; Smits, R.; Hoepping, A.; Steinbach, J.; Sabri, O.; Brust, P. Radiation dosimetry of the alpha4beta2 nicotinic receptor ligand (+)-[18f]flubatine, comparing preclinical PET/MRI and PET/CT to first-in-human PET/CT results. EJNMMI Phys., 2016, 3(1), 1-17.
Karimi, M.; Tu, Z.; Yue, X.; Zhang, X.; Jin, H.; Perlmutter, J.S.; Laforest, R. Radiation dosimetry of [18F]VAT in nonhuman primates. EJNMMI Res., 2015, 5(1), 1-6.
Marti-Climent, J.M.; Collantes, M.; Jauregui-Osoro, M.; Quincoces, G.; Prieto, E.; Bilbao, I.; Ecay, M.; Richter, J.A.; Peñuelas, I. Radiation dosimetry and biodistribution in non-human primates of the sodium/iodide pet ligand [18F]-tetrafluoroborate. EJNMMI Res., 2015, 5(1), 1-9.
Waterhouse, R.N.; Zhao, J.; Stabin, M.G.; Ng, H.; Schindler-Horvat, J.; Chang, R.C.; Mirsalis, J.C. Preclinical acute toxicity studies and dosimetry estimates of the novel sigma-1 receptor radiotracer, [18F]SFE. Mol. Imaging Biol., 2006, 8(5), 284-291.
M3(R2); ICH, E. ICH M3(R2) - Guidance on non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. Int. Conf. Harmon., 2009, pp. 1-25.
Koziorowski, J.; Behe, M.; Decristoforo, C.; Ballinger, J.; Elsinga, P.; Ferrari, V.; Kolenc Peitl, P.; Todde, S.; Mindt, T.L. Position paper on requirements for toxicological studies in the specific case of radiopharmaceuticals. EJNMMI Radiopharm. Chem., 2017, 1(1), 1-6.
Nair, A.B.; Jacob, S. A Simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm., 2016, 7(2), 27-31.
Eckerman, K.; Endo, A. MIRDRadionuclide data and decay schemes 2nd Edn (Reston; VA: Society for nuclear medicine), 2008.
Salabert, A-S.; Mora-Ramirez, E.; Beaurain, M.; Alonso, M.; Fontan, C.; Tahar, H.B.; Boizeau, M.L.; Tafani, M.; Bardiès, M.; Payoux, P. Evaluation of [18F] FNM biodistribution and dosimetry based on whole-body PET imaging of rats. Nucl. Med. Biol., 2018, 59, 1-8.
Mathematica ,Version 10.4; Version 10.4; Champaign, Illinois, 2015.
McParland, B.J. Nuclear Medicine Radiation Dosimetry: Advanced Theoretical Principles; Springer Science & Business Media, 2010.
Stabin, M.G.; Sparks, R.B.; Crowe, E. OLINDA/EXM: The second-generation personal computer software for internal dose assessment in nuclear medicine. J. Nucl. Med., 2005, 46(6), 1023-1027.
Stabin, M.; Siegel, J.A. Radar dose estimate report: A compendium of radiopharmaceutical dose estimates based on Olinda/Exm Version 2.0. J. Nucl. Med., 2018, 59(1), 154-160.
Stabin, M.G.; Xu, X.G.; Emmons, M.A.; Segars, W.P.; Shi, C.; Fernald, M.J. RADAR reference adult, pediatric, and pregnant female phantom series for internal and external dosimetry. J. Nucl. Med., 2012, 53, 1807-1813.
ICRP Basic Anatomical and Physiological Data for Use in Radiological Protection: Reference Values. A Report of Age- and Gender-Related Differences in the Anatomical and Physiological Characteristics of Reference Individuals. ICRP Publication 89. Ann. ICRP, 2002, 32(3-4), 5-265.
Protection, R. ICRP Publication 103. Ann. ICRP, 2007, 37(2.4), 2.
Guerriero, F.; Ferrari, M.E.; Botta, F.; Fioroni, F.; Grassi, E.; Versari, A.; Sarnelli, A.; Pacilio, M.; Amato, E.; Strigari, L.; Bodei, L.; Paganelli, G.; Iori, M.; Pedroli, G.; Cremonesi, M. kidney dosimetry in 177lu and 90y peptide receptor radionuclide therapy: influence of image timing, time-activity integration method, and risk factors. Biomed Res. Int., 2013, 1-12.
Boschi, S.; Lee, J.T.; Beykan, S.; Slavik, R.; Wei, L.; Spick, C.; Eberlein, U.; Buck, A.K.; Lodi, F.; Cicoria, G.; Czernin, J.; Lassmann, M.; Fanti, S.; Herrmann, K. Synthesis and preclinical evaluation of an Al18F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand. Eur. J. Nucl. Med. Mol. Imaging, 2016, 43(12), 2122-2130.
Kranz, M.; Sattler, B.; Wüst, N.; Deuther-Conrad, W.; Patt, M.; Meyer, P.M.; Fischer, S.; Donat, C.K.; Wünsch, B.; Hesse, S.; Steinbach, J.; Brust, P.; Sabri, O. Evaluation of the enantiomer specific biokinetics and radiation doses of [18 F] fluspidine-a new tracer in clinical translation for imaging of Σ1receptors. Molecules, 2016, 2(9), 1164-1178.
Waterhouse, R.N.; Stabin, M.G.; Page, J.G. Preclinical acute toxicity studies and rodent-based dosimetry estimates of the novel sigma-1 receptor radiotracer [18 F] FPS. Nucl. Med. Biol., 2003, 30, 555-563.
Beykan, S.; Dam, J.S.; Eberlein, U.; Kaufmann, J.; Kjærgaard, B.; Jødal, L.; Bouterfa, H.; Lassmann, M.; Jensen, S.B. [177Lu]-OPS201 targeting somatostatin receptors: In vivo biodistribution and dosimetry in a pig model. Eur. J. Nucl. Med. Mol. Imaging, 2016, 6(1), 1-9.

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