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Vol 20, No 2 (2017)
Original articles
Published online: 2017-05-25
Submitted: 2016-12-28
Accepted: 2017-04-25
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New synthesis route of active substance d,l-HMPAO for preparation Technetium Tc99m Exametazime

Justyna Pijarowska-Kruszyna, Urszula Karczmarczyk, Antoni Włodzimierz Jaroń, Ewa Laszuk, Marcin Radzik, Piotr Garnuszek, Renata Mikołajczak
DOI: 10.5603/NMR.2017.0014
·
Pubmed: 28555448
·
Nucl. Med. Rev 2017;20(2):88-94.

open access

Vol 20, No 2 (2017)
Original articles
Published online: 2017-05-25
Submitted: 2016-12-28
Accepted: 2017-04-25

Abstract

BACKGROUND: Technetium Tc99m Exametazime (99mTc-HMPAO) is currently used as a radiopharmaceutical for determining regional cerebral blood flow and for the labelling of autologous leucocytes for infection and inflammation imaging. The HMPAO ligand exists in two diastereomeric forms: d,l and meso. Usually, the substance is obtained in low chemical yield in a time consuming procedure. Furthermore, the final product still contains some amounts of the meso-form. The aim of this study was to develop the efficient, reliable and fast method for isolation of the d,l-HMPAO, which would provide the ligand with high purity and free from the meso-diastereomer.

MATERIAL AND METHODS: The mixture of the meso- and d,l-HMPAO was synthesized in two-steps by condensation of propanediamine with keto-oxime and the reduction of the obtained bisimine. The d- and l-enantiomers were separated individually directly from this mixture by repeated crystallizations from ethanol as their tartrate salts and pooled together in equal proportions. That substance was characterized for its identity and isomeric purity using IR, HPLC and GC methods. The meso-free d,l-HMPAO was used for the preparation of the radiopharmaceutical freeze-dried kit for technetium-99m radiolabelling. Quality assessment of obtained 99mTc-d,l-HMPAO complex was performed according to the current Ph.Eur. monograph 1925 and USP monograph — Technetium Tc99m Exametazime Injection. To verify its biological activity, the kit-prepared 99mTc-d,l-HMPAO has been used for the white blood cell (WBC) labelling.

RESULTS: According to the proposed synthesis route the d,l-HMPAO was obtained with around 18–20% yield in the total time of 10 days. The ligand identity was confirmed and the HPLC analysis revealed more than 99% chemical purity. The undesired meso-form was not detected. Freeze dried kit formulation for 99mTc-labelling of d,l-HMPAO has been established and four batches of kits were manufactured. The radiochemical purity of 99mTc-d,l-HMPAO complex was high (> 95% of lipophilic technetium-99m exametazime). Brain uptake in rats reached 2.1 ± 0.3%. The in vitro labelling of WBC resulted in 68.3 ± 6.6% yield.

CONCLUSION: A new synthesis method of d,l-HMPAO, drug substance for technetium-99m exametazime preparation has been developed.

Abstract

BACKGROUND: Technetium Tc99m Exametazime (99mTc-HMPAO) is currently used as a radiopharmaceutical for determining regional cerebral blood flow and for the labelling of autologous leucocytes for infection and inflammation imaging. The HMPAO ligand exists in two diastereomeric forms: d,l and meso. Usually, the substance is obtained in low chemical yield in a time consuming procedure. Furthermore, the final product still contains some amounts of the meso-form. The aim of this study was to develop the efficient, reliable and fast method for isolation of the d,l-HMPAO, which would provide the ligand with high purity and free from the meso-diastereomer.

MATERIAL AND METHODS: The mixture of the meso- and d,l-HMPAO was synthesized in two-steps by condensation of propanediamine with keto-oxime and the reduction of the obtained bisimine. The d- and l-enantiomers were separated individually directly from this mixture by repeated crystallizations from ethanol as their tartrate salts and pooled together in equal proportions. That substance was characterized for its identity and isomeric purity using IR, HPLC and GC methods. The meso-free d,l-HMPAO was used for the preparation of the radiopharmaceutical freeze-dried kit for technetium-99m radiolabelling. Quality assessment of obtained 99mTc-d,l-HMPAO complex was performed according to the current Ph.Eur. monograph 1925 and USP monograph — Technetium Tc99m Exametazime Injection. To verify its biological activity, the kit-prepared 99mTc-d,l-HMPAO has been used for the white blood cell (WBC) labelling.

RESULTS: According to the proposed synthesis route the d,l-HMPAO was obtained with around 18–20% yield in the total time of 10 days. The ligand identity was confirmed and the HPLC analysis revealed more than 99% chemical purity. The undesired meso-form was not detected. Freeze dried kit formulation for 99mTc-labelling of d,l-HMPAO has been established and four batches of kits were manufactured. The radiochemical purity of 99mTc-d,l-HMPAO complex was high (> 95% of lipophilic technetium-99m exametazime). Brain uptake in rats reached 2.1 ± 0.3%. The in vitro labelling of WBC resulted in 68.3 ± 6.6% yield.

CONCLUSION: A new synthesis method of d,l-HMPAO, drug substance for technetium-99m exametazime preparation has been developed.

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Keywords

99mTc-d,l-HMPAO, chemical synthesis, 99mTc-exametazime, brain SPECT, infection imaging

About this article
Title

New synthesis route of active substance d,l-HMPAO for preparation Technetium Tc99m Exametazime

Journal

Nuclear Medicine Review

Issue

Vol 20, No 2 (2017)

Pages

88-94

Published online

2017-05-25

DOI

10.5603/NMR.2017.0014

Pubmed

28555448

Bibliographic record

Nucl. Med. Rev 2017;20(2):88-94.

Keywords

99mTc-d
l-HMPAO
chemical synthesis
99mTc-exametazime
brain SPECT
infection imaging

Authors

Justyna Pijarowska-Kruszyna
Urszula Karczmarczyk
Antoni Włodzimierz Jaroń
Ewa Laszuk
Marcin Radzik
Piotr Garnuszek
Renata Mikołajczak

References (18)
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