Routine Production of 89Zr Using an Automated Module

Wooten, A.; Madrid, Evelyn; Schweitzer, Gordon; Lawrence, Luke; Mebrahtu, Efrem; Lewis, Benjamin; Lapi, Suzanne

doi:10.3390/app3030593

Title: Routine Production of ⁸⁹Zr Using an Automated Module

Abstract

⁸⁹Zr has emerged as a useful radioisotope for targeted molecular imaging via positron emission tomography (PET) in both animal models and humans. This isotope is particularly attractive for cancer research because its half-life (t_1/2 = 3.27 days) is well-suited for in vivo targeting of macromolecules and nanoparticles to cell surface antigens expressed by cancer cells. Furthermore, ⁸⁹Zr emits a low-energy positron (E_β+,mean = 0.40 MeV), which is favorable for high spatial resolution in PET, with an adequate branching ratio for positron emission (BR = 23%). The demand for ⁸⁹Zr for research purposes is increasing; however, ⁸⁹Zr also emits significant gamma radiation (Γ_{15 keV} = 6.6 R∙cm²/mCi∙h), which makes producing large amounts of this isotope by hand unrealistic from a radiation safety standpoint. Fortunately, a straightforward method exists for production of ⁸⁹Zr by bombarding a natural Y target in a biomedical cyclotron and then separation of ⁸⁹Zr from the target material by column chromatography. The chemical separation in this method lends itself to remote processing using an automated module placed inside a hot cell. In this work, we have designed, built and commissioned a module that has performed the chemical separation of ⁸⁹Zr safely and routinely, at activities in excess ofmore »« less

Authors:

Wooten, A. ^[1]; Madrid, Evelyn ^[2]; Schweitzer, Gordon ^[2]; Lawrence, Luke ^[2]; Mebrahtu, Efrem ^[2]; Lewis, Benjamin ^[3]; Lapi, Suzanne ^[1]

Washington Univ., St. Louis, MO (United States). School of Medicine. Mallinckrodt Inst. of Radiology. Dept. of Biomedical Engineering
Washington Univ., St. Louis, MO (United States). School of Medicine. Mallinckrodt Inst. of Radiology
Washington Univ., St. Louis, MO (United States). School of Medicine. Mallinckrodt Inst. of Radiology. Dept. of Physics

Publication Date:: Fri Jul 12 00:00:00 EDT 2013

Research Org.:: Washington Univ., St. Louis, MO (United States)

Sponsoring Org.:: USDOE National Nuclear Security Administration (NNSA); USDOE Office of Science (SC), Nuclear Physics (NP); National Inst. of Health (NIH) (United States)

OSTI Identifier:: 1454864

Grant/Contract Number:: NA0000979; SC0008657; T32EB014855-01

Resource Type:: Journal Article: Accepted Manuscript

Journal Name:: Applied Sciences

Additional Journal Information:: Journal Volume: 3; Journal Issue: 3; Journal ID: ISSN 2076-3417

Publisher:: MDPI

Country of Publication:: United States

Language:: English

Subject:: 07 ISOTOPE AND RADIATION SOURCES; 89Zr; isotope production; automation; cyclotron; positron emission tomography

Citation Formats


                    Wooten, A., Madrid, Evelyn, Schweitzer, Gordon, Lawrence, Luke, Mebrahtu, Efrem, Lewis, Benjamin, and Lapi, Suzanne. Routine Production of 89Zr Using an Automated Module.  United States: N. p., 2013. 
        Web.  doi:10.3390/app3030593.

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                    Wooten, A., Madrid, Evelyn, Schweitzer, Gordon, Lawrence, Luke, Mebrahtu, Efrem, Lewis, Benjamin, & Lapi, Suzanne. Routine Production of 89Zr Using an Automated Module.  United States.  https://doi.org/10.3390/app3030593

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                    Wooten, A., Madrid, Evelyn, Schweitzer, Gordon, Lawrence, Luke, Mebrahtu, Efrem, Lewis, Benjamin, and Lapi, Suzanne. 2013.  
        "Routine Production of 89Zr Using an Automated Module".  United States.  https://doi.org/10.3390/app3030593.  https://www.osti.gov/servlets/purl/1454864.

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@article{osti_1454864,

  title        = {Routine Production of 89Zr Using an Automated Module},

  author       = {Wooten, A. and Madrid, Evelyn and Schweitzer, Gordon and Lawrence, Luke and Mebrahtu, Efrem and Lewis, Benjamin and Lapi, Suzanne},

  abstractNote = {89Zr has emerged as a useful radioisotope for targeted molecular imaging via positron emission tomography (PET) in both animal models and humans. This isotope is particularly attractive for cancer research because its half-life (t1/2 = 3.27 days) is well-suited for in vivo targeting of macromolecules and nanoparticles to cell surface antigens expressed by cancer cells. Furthermore, 89Zr emits a low-energy positron (Eβ+,mean = 0.40 MeV), which is favorable for high spatial resolution in PET, with an adequate branching ratio for positron emission (BR = 23%). The demand for 89Zr for research purposes is increasing; however, 89Zr also emits significant gamma radiation (Γ15 keV = 6.6 R∙cm2/mCi∙h), which makes producing large amounts of this isotope by hand unrealistic from a radiation safety standpoint. Fortunately, a straightforward method exists for production of 89Zr by bombarding a natural Y target in a biomedical cyclotron and then separation of 89Zr from the target material by column chromatography. The chemical separation in this method lends itself to remote processing using an automated module placed inside a hot cell. In this work, we have designed, built and commissioned a module that has performed the chemical separation of 89Zr safely and routinely, at activities in excess of 50 mCi, with radionuclidic purity > 99.9% and satisfactory effective specific activity (ESA).},

  doi          = {10.3390/app3030593},

  url          = {https://www.osti.gov/biblio/1454864},
  journal      = {Applied Sciences},

  issn         = {2076-3417},

  number       = 3,

  volume       = 3,

  place        = {United States},

  year         = {Fri Jul 12 00:00:00 EDT 2013},

  month        = {Fri Jul 12 00:00:00 EDT 2013}

}

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Zirconium-89 has an ideal half-life for use in antibody-based PET imaging; however, when used with the chelator DFO, there is an accumulation of radioactivity in the bone, suggesting that the ⁸⁹Zr⁴⁺ cation is being released in vivo. Therefore, a more robust chelator for ⁸⁹Zr could reduce the in vivo release and the dose to nontarget tissues. Evaluation of the ligand 3,4,3-(LI-1,2-HOPO) demonstrated efficient binding of ⁸⁹Zr⁴⁺ and high stability; therefore, we developed a bifunctional derivative, p-SCN-Bn-HOPO, for conjugation to an antibody. A Zr-HOPO crystal structure was obtained showing that the Zr is fully coordinated by the octadentate HOPO ligand, asmore »« less
Cited by 83
https://doi.org/10.1021/acs.bioconjchem.5b00572

Full Text Available
Imaging of Fibroblast Activation Protein Alpha Expression in a Preclinical Mouse Model of Glioma Using Positron Emission Tomography

Journal Article Pandya, Darpan; Sinha, Akesh; Yuan, Hong; ... - Molecules

Glioblastoma multiforme (GBM) is the most aggressive glioma of the primary central nervous system. Due to the lack of effective treatment options, the prognosis for patients remains bleak. Fibroblast activation protein alpha (FAP), a 170 kDa type II transmembrane serine protease was observed to be expressed on glioma cells and within the glioma tumor microenvironment. To understand the utility of targeting FAP in this tumor type, the immuno-PET radiopharmaceutical [⁸⁹Zr]Zr-Df-Bz-F19 mAb was prepared and Lindmo analysis was used for its in vitro evaluation using the U87MG cell line, which expresses FAP endogenously. Lindmo analysis revealed an association constant (K_a) ofmore »« less
https://doi.org/10.3390/molecules25163672

Full Text Available

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Title: Routine Production of 89Zr Using an Automated Module

Abstract

Citation Formats

Evaluation of desferal as a bifunctional chelating agent for labeling antibodies with Zr-89 journal, December 1992

Standardized methods for the production of high specific-activity zirconium-89 journal, October 2009

Investigations of 89Y(p,x)86,88,89gZr, 86m+g,87g,87m,88gY, 85gSr, and 84gRb nuclear processes up to 42MeV journal, January 2012

Survey of ( p , n ) Reactions at 12 Mev journal, December 1955

Nuclear reactions in Rb, Sr, Y, and Zr targets journal, September 1982

Reactions (p, pn), (p, 2n) and (p, n) on 89Y induced by high-energy protons journal, June 1966

Excitation Functions of Proton Induced Reactions on 89Y and 93Nb with Emphasis on the Production of Selected Radio-Zirconiums journal, August 2011

Excitation Functions for Production of 88Zr and 88Y by Proton and Deuteron Irradiation of Mo, Nb, Zr, and Y conference, January 2005

Unconventional Nuclides for Radiopharmaceuticals journal, January 2010

Simultaneous production of 89Zr and 90,91m,92mNb in α-particle activated yttrium and their subsequent separation by HDEHP journal, July 1997

The rise of metal radionuclides in medical imaging: copper-64, zirconium-89 and yttrium-86 journal, April 2011

Radioimmunoimaging with Longer-Lived Positron-Emitting Radionuclides: Potentials and Challenges journal, May 2009

PET Tracers Based on Zirconium-89 journal, April 2011

Fully automated production of iodine-124 using a vertical beam journal, January 2011

Automated production of copper radioisotopes and preparation of high specific activity [64Cu]Cu-ATSM for PET studies journal, January 2010

Proton induced reactions on 89Y with particular reference to the production of the medically interesting radionuclide 89Zr journal, January 2009

Production of 88,89Zr by proton induced activation of natY and separation by SLX and LLX journal, June 2009

An automated method for regular productions of copper-64 for PET radiopharmaceuticals journal, April 2010

Implementation of 89Zr production and in vivo imaging of B-cells in mice with 89Zr-labeled anti-B-cell antibodies by small animal PET/CT journal, June 2011

Immuno-PET: A Navigator in Monoclonal Antibody Development and Applications journal, December 2007

89Zr Radiochemistry for Positron Emission Tomography journal, September 2011

PET imaging with 89Zr: From radiochemistry to the clinic journal, January 2013

Pre-equilibrium processes in (p,n) reactions journal, February 1973

Measurements and a direct-reaction – plus – Hauser-Feshbach analysis of Y 89 ( p , n ) 89 Zr, Y 89 ( p ,2 n ) 88 , and Y 89 ( p , pn ) 88 Y reactions up to 40 MeV journal, October 1988

Image-Quality Assessment for Several Positron Emitters Using the NEMA NU 4-2008 Standards in the Siemens Inveon Small-Animal PET Scanner journal, March 2010

Manganese-52m for direct application: A new 52Fe/52mMn generator based on a hydroxamate resin journal, June 1983

Preparation, properties and analytical application of silica with chemically grafted hydroxamic acid groups journal, January 1989

Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of Disease journal, May 2010

( p , xn ) and ( p , pxn ) Reactions of Yttrium-89 with 5-85-MeV Protons journal, April 1966

89Zr-PET Radiochemistry in the Development and Application of Therapeutic Monoclonal Antibodies and Other Biologicals journal, March 2013

Positive Progress in ImmunoPET—Not Just a Coincidence journal, June 2010

Review on Production of 89Zr in a Medical Cyclotron for PET Radiopharmaceuticals journal, January 2013

A comparative study on the separation of radiozirconium via ion-exchange and solvent extraction techniques, with particular reference to the production of 88Zr and 89Zr in proton induced reactions on yttrium journal, October 2007

Study of ( p , x n ) Reactions at 400 MeV journal, February 1969

Exposure rate Constants and lead Shielding Values for over 1,100 Radionuclides journal, January 2012

A computerized compact module for separation of 99mTc-radionuclide from molybdenum journal, November 2012

Interaction of Yttrium with Protons of Energy between 60 and 240 Mev journal, September 1959

Semi-automated 86Y purification using a three-column system journal, February 2004

A peristaltic pump driven [sup 89]Zr separation module conference, January 2012

Immuno-Positron Emission Tomography: Shedding Light on Clinical Antibody Therapy journal, August 2010

An automated system for production of [sup 89]Zr conference, January 2012

Production of no-carrier-added zirconium-89 for positron emission tomography journal, January 1991

Cross sections for the production of residual nuclides by low- and medium-energy protons from the target elements C, N, O, Mg, Al, Si, Ca, Ti, V, Mn, Fe, Co, Ni, Cu, Sr, Y, Zr, Nb, Ba and Au journal, July 1997

Radiometal-Labeled Agents (Non-Technetium) for Diagnostic Imaging journal, September 1999

A semi-automated system for the routine production of copper-64 journal, August 2012

Production of highly pure no-carrier added 89Zr for the labelling of antibodies with a positron emitter journal, December 1994

Experimental studies on excitation functions of the proton-induced activation reactions on yttrium journal, September 2005

Production and purification of 89Zr, a potential PET antibody label journal, January 1990

Automated production of copper radioisotopes and preparation of high specific activity [64Cu]Cu-ATSM for PET studies journal, January 2010

A computerized compact module for separation of 99mTc-radionuclide from molybdenum journal, November 2012

Radioimmunoimaging with Longer-Lived Positron-Emitting Radionuclides: Potentials and Challenges journal, May 2009

Radiometals for imaging and theranostics, current production, and future perspectives journal, July 2019

[89Zr]Trastuzumab: Evaluation of Radiation Dosimetry, Safety, and Optimal Imaging Parameters in Women with HER2-Positive Breast Cancer journal, May 2016

Targeting HER2 in Nuclear Medicine for Imaging and Therapy journal, January 2018

Comparative Study with 89Y-foil and 89Y-pressed Targets for the Production of 89Zr † journal, September 2018

Medical Cyclotron Solid Target Preparation by Ultrathick Film Magnetron Sputtering Deposition journal, March 2019

Evaluation of 89Zr-pertuzumab in Breast Cancer Xenografts journal, August 2014

Zirconium-89 Labeled Antibodies: A New Tool for Molecular Imaging in Cancer Patients journal, January 2014

Targeting HER2 in Nuclear Medicine for Imaging and Therapy journal, January 2018

Development of 89Zr-Ontuxizumab for in vivo TEM-1/endosialin PET applications journal, February 2016

Microfluidic Preparation of a 89 Zr-Labeled Trastuzumab Single-Patient Dose journal, January 2016

Recent Advances in Zirconium-89 Chelator Development journal, March 2018

Title: Routine Production of ⁸⁹Zr Using an Automated Module

Evaluation of desferal as a bifunctional chelating agent for labeling antibodies with Zr-89
journal, December 1992

Standardized methods for the production of high specific-activity zirconium-89
journal, October 2009

Investigations of 89Y(p,x)86,88,89gZr, 86m+g,87g,87m,88gY, 85gSr, and 84gRb nuclear processes up to 42MeV
journal, January 2012

Survey of ( $p, n$ ) Reactions at 12 Mev
journal, December 1955

Nuclear reactions in Rb, Sr, Y, and Zr targets
journal, September 1982

Reactions (p, pn), (p, 2n) and (p, n) on 89Y induced by high-energy protons
journal, June 1966

Excitation Functions of Proton Induced Reactions on 89Y and 93Nb with Emphasis on the Production of Selected Radio-Zirconiums
journal, August 2011

Excitation Functions for Production of 88Zr and 88Y by Proton and Deuteron Irradiation of Mo, Nb, Zr, and Y
conference, January 2005

Unconventional Nuclides for Radiopharmaceuticals
journal, January 2010

Simultaneous production of 89Zr and 90,91m,92mNb in α-particle activated yttrium and their subsequent separation by HDEHP
journal, July 1997

The rise of metal radionuclides in medical imaging: copper-64, zirconium-89 and yttrium-86
journal, April 2011

Radioimmunoimaging with Longer-Lived Positron-Emitting Radionuclides: Potentials and Challenges
journal, May 2009

PET Tracers Based on Zirconium-89
journal, April 2011

Fully automated production of iodine-124 using a vertical beam
journal, January 2011

Automated production of copper radioisotopes and preparation of high specific activity [64Cu]Cu-ATSM for PET studies
journal, January 2010

Proton induced reactions on 89Y with particular reference to the production of the medically interesting radionuclide 89Zr
journal, January 2009

Production of 88,89Zr by proton induced activation of natY and separation by SLX and LLX
journal, June 2009

An automated method for regular productions of copper-64 for PET radiopharmaceuticals
journal, April 2010

Implementation of 89Zr production and in vivo imaging of B-cells in mice with 89Zr-labeled anti-B-cell antibodies by small animal PET/CT
journal, June 2011

Immuno-PET: A Navigator in Monoclonal Antibody Development and Applications
journal, December 2007

89Zr Radiochemistry for Positron Emission Tomography
journal, September 2011

PET imaging with 89Zr: From radiochemistry to the clinic
journal, January 2013

Pre-equilibrium processes in (p,n) reactions
journal, February 1973

Measurements and a direct-reaction – plus – Hauser-Feshbach analysis of ${}^{89}Y$ ( p , n $)^{89}$ Zr, ${}^{89}Y$ ( p ,2 n $)^{88}$ , and ${}^{89}Y$ ( p , pn $)^{88}$ Y reactions up to 40 MeV
journal, October 1988

Image-Quality Assessment for Several Positron Emitters Using the NEMA NU 4-2008 Standards in the Siemens Inveon Small-Animal PET Scanner
journal, March 2010

Manganese-52m for direct application: A new 52Fe/52mMn generator based on a hydroxamate resin
journal, June 1983

Preparation, properties and analytical application of silica with chemically grafted hydroxamic acid groups
journal, January 1989

Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of Disease
journal, May 2010

( $p, xn$ ) and ( $p, pxn$ ) Reactions of Yttrium-89 with 5-85-MeV Protons
journal, April 1966

⁸⁹Zr-PET Radiochemistry in the Development and Application of Therapeutic Monoclonal Antibodies and Other Biologicals
journal, March 2013

Positive Progress in ImmunoPET—Not Just a Coincidence
journal, June 2010

Review on Production of 89Zr in a Medical Cyclotron for PET Radiopharmaceuticals
journal, January 2013

A comparative study on the separation of radiozirconium via ion-exchange and solvent extraction techniques, with particular reference to the production of 88Zr and 89Zr in proton induced reactions on yttrium
journal, October 2007

Study of ( $p, x n$ ) Reactions at 400 MeV
journal, February 1969

Exposure rate Constants and lead Shielding Values for over 1,100 Radionuclides
journal, January 2012

A computerized compact module for separation of 99mTc-radionuclide from molybdenum
journal, November 2012

Interaction of Yttrium with Protons of Energy between 60 and 240 Mev
journal, September 1959

Semi-automated 86Y purification using a three-column system
journal, February 2004

A peristaltic pump driven [sup 89]Zr separation module
conference, January 2012

Immuno-Positron Emission Tomography: Shedding Light on Clinical Antibody Therapy
journal, August 2010

An automated system for production of [sup 89]Zr
conference, January 2012

Production of no-carrier-added zirconium-89 for positron emission tomography
journal, January 1991

Cross sections for the production of residual nuclides by low- and medium-energy protons from the target elements C, N, O, Mg, Al, Si, Ca, Ti, V, Mn, Fe, Co, Ni, Cu, Sr, Y, Zr, Nb, Ba and Au
journal, July 1997

Radiometal-Labeled Agents (Non-Technetium) for Diagnostic Imaging
journal, September 1999

A semi-automated system for the routine production of copper-64
journal, August 2012

Production of highly pure no-carrier added 89Zr for the labelling of antibodies with a positron emitter
journal, December 1994

Experimental studies on excitation functions of the proton-induced activation reactions on yttrium
journal, September 2005

Production and purification of 89Zr, a potential PET antibody label
journal, January 1990

Automated production of copper radioisotopes and preparation of high specific activity [64Cu]Cu-ATSM for PET studies
journal, January 2010

A computerized compact module for separation of 99mTc-radionuclide from molybdenum
journal, November 2012

Radioimmunoimaging with Longer-Lived Positron-Emitting Radionuclides: Potentials and Challenges
journal, May 2009

Radiometals for imaging and theranostics, current production, and future perspectives
journal, July 2019

[89Zr]Trastuzumab: Evaluation of Radiation Dosimetry, Safety, and Optimal Imaging Parameters in Women with HER2-Positive Breast Cancer
journal, May 2016

Targeting HER2 in Nuclear Medicine for Imaging and Therapy
journal, January 2018

Comparative Study with 89Y-foil and 89Y-pressed Targets for the Production of 89Zr †
journal, September 2018

Medical Cyclotron Solid Target Preparation by Ultrathick Film Magnetron Sputtering Deposition
journal, March 2019

Evaluation of ⁸⁹Zr-pertuzumab in Breast Cancer Xenografts
journal, August 2014

Zirconium-89 Labeled Antibodies: A New Tool for Molecular Imaging in Cancer Patients
journal, January 2014

Targeting HER2 in Nuclear Medicine for Imaging and Therapy
journal, January 2018

Development of 89Zr-Ontuxizumab for in vivo TEM-1/endosialin PET applications
journal, February 2016

Microfluidic Preparation of a ⁸⁹ Zr-Labeled Trastuzumab Single-Patient Dose
journal, January 2016

Recent Advances in Zirconium-89 Chelator Development
journal, March 2018