Preparation and preliminary evaluation of 63Zn-zinc citrate as a novel PET imaging biomarker for zinc

Timothy R DeGrado, Mukesh Pandey, John F. Byrne, Hendrik P. Engelbrecht, Huailei Jiang, Alan B. Packard, Kevin A. Thomas, Mark S. Jacobson, Geoffrey L. Curran, Val Lowe

Research output: Contribution to journalArticle

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Abstract

Abnormalities of zinc homeostasis are indicated in many human diseases. A noninvasive imaging method for monitoring zinc in the body would be useful to understand zinc dynamics in health and disease. To provide a PET imaging agent for zinc, we have investigated production of 63Zn (half-life, 38.5 min) via the 63Cu(p,n)63Zn reaction using isotopically enriched solutions of 63Cu-copper nitrate. A solution target was used for rapid isolation of the 63Zn radioisotope from the parent 63Cu ions. Initial biologic evaluation was performed by biodistribution and PET imaging in normal mice. Methods: To produce 63Zn, solutions of 63Cu-copper nitrate in dilute nitric acid were irradiated by 14-MeV protons in a low-energy cyclotron. An automated module was used to purify 63Zn from 63Cu in the target solution. The 63Cu-63Zn mixture was trapped on a cation-exchange resin and rinsed with water, and the 63Zn was eluted using 0.05 N HCl in 90% acetone. The resulting solution was neutralized with NaHCO3, and the 63Zn was then trapped on a carboxymethyl cartridge, washed with water, and eluted with isotonic 4% sodium citrate. Standard quality control tests were performed on the product according to current good manufacturing practice, including radionuclidic identity and purity, and measurement of nonradioactive Zn+2, Cu+2, Fe+3, and Ni+2by ion-chromatography high-performance liquid chroma-tography. Biodistribution and PET imaging studies were performed in B6.SJL mice after intravenous administration of 63Zn-zinc citrate. 63Cu target material was recycled by eluting the initial resin with 4N HNO3. Results: Yields of 1.07 ± 0.22 GBq (uncorrected at 30-36 min after end of bombardment) of 63Zn-zinc citrate were obtained with a 1.23 M 63Cu-copper nitrate solution. Radionuclidic purity was greater than 99.9%, with copper content lower than 3 μg/batch. Specific activities were 41.2 ± 18.1 MBq/μg (uncorrected) for the 63Zn product. PET and biodistribution studies in mice at 60 min showed expected high uptake in the pancreas (standard uptake value, 8.8 ± 3.2), liver (6.0 ± 1.9), upper intestine (4.7 ± 2.1), and kidney (4.2 ± 1.3). Conclusion: A practical and current good manufacturing practice-compliant preparation of radionuclidically pure 63Zn-zinc citrate has been developed that will enable PET imaging studies in animal and human studies. 63Zn-zinc citrate showed the expected biodistribution in mice. COPYRIGHT

Original languageEnglish (US)
Pages (from-to)1348-1354
Number of pages7
JournalJournal of Nuclear Medicine
Volume55
Issue number8
DOIs
StatePublished - Aug 1 2014

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Citric Acid
Zinc
Biomarkers
Copper
Nitrates
Cation Exchange Resins
Ions
Cyclotrons
Nitric Acid
Water
Acetone
Radioisotopes
Quality Control
Intravenous Administration
Intestines
Half-Life
Protons
Pancreas
Homeostasis
High Pressure Liquid Chromatography

Keywords

  • PET
  • Radioisotope production
  • Solution target

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Preparation and preliminary evaluation of 63Zn-zinc citrate as a novel PET imaging biomarker for zinc. / DeGrado, Timothy R; Pandey, Mukesh; Byrne, John F.; Engelbrecht, Hendrik P.; Jiang, Huailei; Packard, Alan B.; Thomas, Kevin A.; Jacobson, Mark S.; Curran, Geoffrey L.; Lowe, Val.

In: Journal of Nuclear Medicine, Vol. 55, No. 8, 01.08.2014, p. 1348-1354.

Research output: Contribution to journalArticle

DeGrado, Timothy R ; Pandey, Mukesh ; Byrne, John F. ; Engelbrecht, Hendrik P. ; Jiang, Huailei ; Packard, Alan B. ; Thomas, Kevin A. ; Jacobson, Mark S. ; Curran, Geoffrey L. ; Lowe, Val. / Preparation and preliminary evaluation of 63Zn-zinc citrate as a novel PET imaging biomarker for zinc. In: Journal of Nuclear Medicine. 2014 ; Vol. 55, No. 8. pp. 1348-1354.
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abstract = "Abnormalities of zinc homeostasis are indicated in many human diseases. A noninvasive imaging method for monitoring zinc in the body would be useful to understand zinc dynamics in health and disease. To provide a PET imaging agent for zinc, we have investigated production of 63Zn (half-life, 38.5 min) via the 63Cu(p,n)63Zn reaction using isotopically enriched solutions of 63Cu-copper nitrate. A solution target was used for rapid isolation of the 63Zn radioisotope from the parent 63Cu ions. Initial biologic evaluation was performed by biodistribution and PET imaging in normal mice. Methods: To produce 63Zn, solutions of 63Cu-copper nitrate in dilute nitric acid were irradiated by 14-MeV protons in a low-energy cyclotron. An automated module was used to purify 63Zn from 63Cu in the target solution. The 63Cu-63Zn mixture was trapped on a cation-exchange resin and rinsed with water, and the 63Zn was eluted using 0.05 N HCl in 90{\%} acetone. The resulting solution was neutralized with NaHCO3, and the 63Zn was then trapped on a carboxymethyl cartridge, washed with water, and eluted with isotonic 4{\%} sodium citrate. Standard quality control tests were performed on the product according to current good manufacturing practice, including radionuclidic identity and purity, and measurement of nonradioactive Zn+2, Cu+2, Fe+3, and Ni+2by ion-chromatography high-performance liquid chroma-tography. Biodistribution and PET imaging studies were performed in B6.SJL mice after intravenous administration of 63Zn-zinc citrate. 63Cu target material was recycled by eluting the initial resin with 4N HNO3. Results: Yields of 1.07 ± 0.22 GBq (uncorrected at 30-36 min after end of bombardment) of 63Zn-zinc citrate were obtained with a 1.23 M 63Cu-copper nitrate solution. Radionuclidic purity was greater than 99.9{\%}, with copper content lower than 3 μg/batch. Specific activities were 41.2 ± 18.1 MBq/μg (uncorrected) for the 63Zn product. PET and biodistribution studies in mice at 60 min showed expected high uptake in the pancreas (standard uptake value, 8.8 ± 3.2), liver (6.0 ± 1.9), upper intestine (4.7 ± 2.1), and kidney (4.2 ± 1.3). Conclusion: A practical and current good manufacturing practice-compliant preparation of radionuclidically pure 63Zn-zinc citrate has been developed that will enable PET imaging studies in animal and human studies. 63Zn-zinc citrate showed the expected biodistribution in mice. COPYRIGHT",
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AU - Pandey, Mukesh

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AU - Engelbrecht, Hendrik P.

AU - Jiang, Huailei

AU - Packard, Alan B.

AU - Thomas, Kevin A.

AU - Jacobson, Mark S.

AU - Curran, Geoffrey L.

AU - Lowe, Val

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N2 - Abnormalities of zinc homeostasis are indicated in many human diseases. A noninvasive imaging method for monitoring zinc in the body would be useful to understand zinc dynamics in health and disease. To provide a PET imaging agent for zinc, we have investigated production of 63Zn (half-life, 38.5 min) via the 63Cu(p,n)63Zn reaction using isotopically enriched solutions of 63Cu-copper nitrate. A solution target was used for rapid isolation of the 63Zn radioisotope from the parent 63Cu ions. Initial biologic evaluation was performed by biodistribution and PET imaging in normal mice. Methods: To produce 63Zn, solutions of 63Cu-copper nitrate in dilute nitric acid were irradiated by 14-MeV protons in a low-energy cyclotron. An automated module was used to purify 63Zn from 63Cu in the target solution. The 63Cu-63Zn mixture was trapped on a cation-exchange resin and rinsed with water, and the 63Zn was eluted using 0.05 N HCl in 90% acetone. The resulting solution was neutralized with NaHCO3, and the 63Zn was then trapped on a carboxymethyl cartridge, washed with water, and eluted with isotonic 4% sodium citrate. Standard quality control tests were performed on the product according to current good manufacturing practice, including radionuclidic identity and purity, and measurement of nonradioactive Zn+2, Cu+2, Fe+3, and Ni+2by ion-chromatography high-performance liquid chroma-tography. Biodistribution and PET imaging studies were performed in B6.SJL mice after intravenous administration of 63Zn-zinc citrate. 63Cu target material was recycled by eluting the initial resin with 4N HNO3. Results: Yields of 1.07 ± 0.22 GBq (uncorrected at 30-36 min after end of bombardment) of 63Zn-zinc citrate were obtained with a 1.23 M 63Cu-copper nitrate solution. Radionuclidic purity was greater than 99.9%, with copper content lower than 3 μg/batch. Specific activities were 41.2 ± 18.1 MBq/μg (uncorrected) for the 63Zn product. PET and biodistribution studies in mice at 60 min showed expected high uptake in the pancreas (standard uptake value, 8.8 ± 3.2), liver (6.0 ± 1.9), upper intestine (4.7 ± 2.1), and kidney (4.2 ± 1.3). Conclusion: A practical and current good manufacturing practice-compliant preparation of radionuclidically pure 63Zn-zinc citrate has been developed that will enable PET imaging studies in animal and human studies. 63Zn-zinc citrate showed the expected biodistribution in mice. COPYRIGHT

AB - Abnormalities of zinc homeostasis are indicated in many human diseases. A noninvasive imaging method for monitoring zinc in the body would be useful to understand zinc dynamics in health and disease. To provide a PET imaging agent for zinc, we have investigated production of 63Zn (half-life, 38.5 min) via the 63Cu(p,n)63Zn reaction using isotopically enriched solutions of 63Cu-copper nitrate. A solution target was used for rapid isolation of the 63Zn radioisotope from the parent 63Cu ions. Initial biologic evaluation was performed by biodistribution and PET imaging in normal mice. Methods: To produce 63Zn, solutions of 63Cu-copper nitrate in dilute nitric acid were irradiated by 14-MeV protons in a low-energy cyclotron. An automated module was used to purify 63Zn from 63Cu in the target solution. The 63Cu-63Zn mixture was trapped on a cation-exchange resin and rinsed with water, and the 63Zn was eluted using 0.05 N HCl in 90% acetone. The resulting solution was neutralized with NaHCO3, and the 63Zn was then trapped on a carboxymethyl cartridge, washed with water, and eluted with isotonic 4% sodium citrate. Standard quality control tests were performed on the product according to current good manufacturing practice, including radionuclidic identity and purity, and measurement of nonradioactive Zn+2, Cu+2, Fe+3, and Ni+2by ion-chromatography high-performance liquid chroma-tography. Biodistribution and PET imaging studies were performed in B6.SJL mice after intravenous administration of 63Zn-zinc citrate. 63Cu target material was recycled by eluting the initial resin with 4N HNO3. Results: Yields of 1.07 ± 0.22 GBq (uncorrected at 30-36 min after end of bombardment) of 63Zn-zinc citrate were obtained with a 1.23 M 63Cu-copper nitrate solution. Radionuclidic purity was greater than 99.9%, with copper content lower than 3 μg/batch. Specific activities were 41.2 ± 18.1 MBq/μg (uncorrected) for the 63Zn product. PET and biodistribution studies in mice at 60 min showed expected high uptake in the pancreas (standard uptake value, 8.8 ± 3.2), liver (6.0 ± 1.9), upper intestine (4.7 ± 2.1), and kidney (4.2 ± 1.3). Conclusion: A practical and current good manufacturing practice-compliant preparation of radionuclidically pure 63Zn-zinc citrate has been developed that will enable PET imaging studies in animal and human studies. 63Zn-zinc citrate showed the expected biodistribution in mice. COPYRIGHT

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