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Improved radiolabeling of DOTATOC with trivalent radiometals for clinical application by addition of ethanol

BACKGROUND: Typically, metal-based radiopharmaceuticals are synthesized in aqueous solutions with no or low ethanol content. Labeling yields are defined by temperature, period of labeling, amount of precursor, pH etc. As recently observed, radiolabeling yields (RCY) seem to increase in the presence...

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Autores principales: Eppard, Elisabeth, Pèrez-Malo, Marylaine, Rösch, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843808/
https://www.ncbi.nlm.nih.gov/pubmed/29564383
http://dx.doi.org/10.1186/s41181-016-0010-8
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author Eppard, Elisabeth
Pèrez-Malo, Marylaine
Rösch, Frank
author_facet Eppard, Elisabeth
Pèrez-Malo, Marylaine
Rösch, Frank
author_sort Eppard, Elisabeth
collection PubMed
description BACKGROUND: Typically, metal-based radiopharmaceuticals are synthesized in aqueous solutions with no or low ethanol content. Labeling yields are defined by temperature, period of labeling, amount of precursor, pH etc. As recently observed, radiolabeling yields (RCY) seem to increase in the presence of non-aqueous solvents. Consequently, this effect was investigated systematically using ethanol as non-aqueous solvent (n-as), which is widely utilized in medicine, and DOTATOC as model compound. METHODS: To determine the impact of ethanol on the radiolabeling efficacy, “standard” labeling conditions of (68)Ga-DOTATOC (95–100 °C, 10–15 min, 20–50 μg DOTATOC, aqueous solution), i.e. 10 nmol (2.9 μM, 14.2 μg), were modified in terms of lower temperature (70 °C) to achieve lower RCY (<75 %). From those lower RCY, positive effects of increasing amounts of ethanol (0–40 vol%) could directly be observed. Labeling parameters were finally evaluated in terms of shorter reaction time and lower amount of precursor. To investigate whether the effects observed are also true for other trivalent radiometals, labeling was also performed with (44)Sc. RESULTS: For increasing amounts of ethanol, (68)Ga-DOTATOC RCY at 70 °C improved significantly. RCY of ~95 % can be achieved within 10 min using 30 vol% ethanol compared to 46 % in the pure aqueous system. If “standard” temperatures of 95 °C are applied, high RCY of 89 % can be achieved within 5 min with much lower amounts of precursor, i.e. even at 0.93 nmol (0.3 μM, 1.3 μg). This also represents significantly increased specific activities. Similar behavior was observed for (44)Sc where RCY increase successively with increasing amounts of ethanol. CONCLUSION: There is clear experimental evidence, that adding more than 20 vol% ethanol to the reaction mixtures significantly improve labeling efficacies. This could be demonstrated for (68)Ga-DOTATOC and (44)Sc-DOTATOC in terms of temperature, time and concentration of required precursor. Whether this is a principal phenomenon with practical impact on the radiopharmaceutical chemistry of trivalent metals and whether this applies to other non-aqueous solvents as well - and what the physico-chemical reasons are, remains to be studied in more detail. Nevertheless, the effect observed here will improve (68)Ga-DOTATOC labeling and may save at least half of the usually applied amount of precursor.
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spelling pubmed-58438082018-03-19 Improved radiolabeling of DOTATOC with trivalent radiometals for clinical application by addition of ethanol Eppard, Elisabeth Pèrez-Malo, Marylaine Rösch, Frank EJNMMI Radiopharm Chem Research BACKGROUND: Typically, metal-based radiopharmaceuticals are synthesized in aqueous solutions with no or low ethanol content. Labeling yields are defined by temperature, period of labeling, amount of precursor, pH etc. As recently observed, radiolabeling yields (RCY) seem to increase in the presence of non-aqueous solvents. Consequently, this effect was investigated systematically using ethanol as non-aqueous solvent (n-as), which is widely utilized in medicine, and DOTATOC as model compound. METHODS: To determine the impact of ethanol on the radiolabeling efficacy, “standard” labeling conditions of (68)Ga-DOTATOC (95–100 °C, 10–15 min, 20–50 μg DOTATOC, aqueous solution), i.e. 10 nmol (2.9 μM, 14.2 μg), were modified in terms of lower temperature (70 °C) to achieve lower RCY (<75 %). From those lower RCY, positive effects of increasing amounts of ethanol (0–40 vol%) could directly be observed. Labeling parameters were finally evaluated in terms of shorter reaction time and lower amount of precursor. To investigate whether the effects observed are also true for other trivalent radiometals, labeling was also performed with (44)Sc. RESULTS: For increasing amounts of ethanol, (68)Ga-DOTATOC RCY at 70 °C improved significantly. RCY of ~95 % can be achieved within 10 min using 30 vol% ethanol compared to 46 % in the pure aqueous system. If “standard” temperatures of 95 °C are applied, high RCY of 89 % can be achieved within 5 min with much lower amounts of precursor, i.e. even at 0.93 nmol (0.3 μM, 1.3 μg). This also represents significantly increased specific activities. Similar behavior was observed for (44)Sc where RCY increase successively with increasing amounts of ethanol. CONCLUSION: There is clear experimental evidence, that adding more than 20 vol% ethanol to the reaction mixtures significantly improve labeling efficacies. This could be demonstrated for (68)Ga-DOTATOC and (44)Sc-DOTATOC in terms of temperature, time and concentration of required precursor. Whether this is a principal phenomenon with practical impact on the radiopharmaceutical chemistry of trivalent metals and whether this applies to other non-aqueous solvents as well - and what the physico-chemical reasons are, remains to be studied in more detail. Nevertheless, the effect observed here will improve (68)Ga-DOTATOC labeling and may save at least half of the usually applied amount of precursor. Springer International Publishing 2016-04-01 /pmc/articles/PMC5843808/ /pubmed/29564383 http://dx.doi.org/10.1186/s41181-016-0010-8 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Research
Eppard, Elisabeth
Pèrez-Malo, Marylaine
Rösch, Frank
Improved radiolabeling of DOTATOC with trivalent radiometals for clinical application by addition of ethanol
title Improved radiolabeling of DOTATOC with trivalent radiometals for clinical application by addition of ethanol
title_full Improved radiolabeling of DOTATOC with trivalent radiometals for clinical application by addition of ethanol
title_fullStr Improved radiolabeling of DOTATOC with trivalent radiometals for clinical application by addition of ethanol
title_full_unstemmed Improved radiolabeling of DOTATOC with trivalent radiometals for clinical application by addition of ethanol
title_short Improved radiolabeling of DOTATOC with trivalent radiometals for clinical application by addition of ethanol
title_sort improved radiolabeling of dotatoc with trivalent radiometals for clinical application by addition of ethanol
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843808/
https://www.ncbi.nlm.nih.gov/pubmed/29564383
http://dx.doi.org/10.1186/s41181-016-0010-8
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