radioisotope development - triumf · 2013-11-14 · radioisotope development . international peer...

Owned and operated as a joint venture by a consortium of Canadian universities via a contribution through the National Research Council Canada Propriété d’un consortium d’universités canadiennes, géré en co-entreprise à partir d’une contribution administrée par le Conseil national de recherches Canada

Canada’s national laboratory for particle and nuclear physics Laboratoire national canadien pour la recherche en physique nucléaire

et en physique des particules

Accelerating Science for Canada Un accélérateur de la démarche scientifique canadienne

Radioisotope Development

International Peer Review 2013

Ken Buckley | Project Manager | TRIUMF

• Production of Tc-99m with small medical cyclotrons • Funded by Natural Resources Canada • NRU reactor to cease Mo-99 production in 2016 • Initiative to diversify the supply of Mo-99 and/or Tc-

99m • Production of radiometals by liquid targets

• Funded as a Collaborative Health Research Project by Canadian Institutes of Health Research

• Improve access to emerging and novel radiometals to enable ‘probe & isotope pair’ research

Introduction

November 14, 2013 Radioisotope Development 2

Cyclotron Tc-99m

November 14, 2013

Radioisotope Development 3

TRIUMF Paul Schaffer (PI), Tom Ruth, Stefan Zeisler, Vicky Hanemaayer, Maurice Dodd, Stuart McDiarmid, Brian Hook, Tom Morley, Conny Hoehr, Mark Preddy, Juergen Kaefer, Mahendra Rathod, Keiler Totz

British Columbia Cancer Agency Francois Benard, Jean-Pierre Appiah, Milan Vuckovic, Julius Klug, Kuo-Shyan Lin, Guillaume Langlois, Wade English, Philip Tsao

Centre for Probe Development and Commercialization

Chris Leon, Constantinos Economou, John Valliant, Bart Bycinzski, Joe McCann, Neil Cockburn, Anne Goodbody, Ravinder de Silva, Ross Harper

Lawson Health Research Institute Mike Kovacs, Jeff Corsaut, Jean-Yves Kazock, Laura Close, Frank Prato

University of British Columbia Anna Celler, Xinchi Hou, Ed Asselin, Leah Penner, Jesse Tanguay

Legend: Student Post-doc Trained through TRIUMF

• 100Mo(p,2n)99mTc • Use existing PET (16-19 MeV) cyclotrons • Solid target irradiation systems

• GE PETtrace cyclotron • ACSI TRPET cyclotron

• Mo-100 coated target plate • Molybdenum dissolution system • Purification of Tc-99m from moly solution

• Recycling of Mo-100 • Regulatory approval for human use • Commercialization of technology and/or production

Project scope

November 14, 2013


Beaver and Hupf, JNM Vol. 12, pp 739-741, 1971.

Reactions on 100Mo

November 14, 2013


Celler et al., Phys. Med. Biol. Vol. 56, pp 5469-5484, 2011.

Isotope Natural Batch 1 Batch 2 Batch 3 Mo-100 9.63 99.01 97.39 99.815 Mo-98 24.13 0.55 2.58 0.17 Mo-97 9.55 0.08 0.01 0.003 Mo-96 16.68 0.11 0.005 0.003 Mo-95 15.92 0.10 0.005 0.003 Mo-94 9.25 0.06 0.005 0.003 Mo-92 14.85 0.09 0.005 0.003

• Mo-100 enrichment is not the whole story

• Critical Tc radionuclidic purity is determined by masses < 98 due to patient dose

• Cost $0.50 - $1.65 per mg

Reactions on 100Mo Reactions on all Mo

PETtrace

November 14, 2013


•Limited space •~ shoebox size

•Single penetration for transfer tube <50 mm diameter •Mo-100 plate orthogonal to beam •Open to cyclotron vacuum

CPDC Site

November 14, 2013


Processing Hot cell

Cyclotron

Total route ~ 12.5 m (one floor elevation change)

Shielding Vault

ACSI TRPET cyclotron

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• Need robust adherent layer, no additives • Form a suspension in a polar organic solvent • Apply voltage and deposit material to depletion

Electrophoretic Deposition

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Journal of the Electrochemical Society, Vol. 109, No. 10, October 1962. Hanemaayer et al., Journal of Radioanalytical and Nuclear Chemistry, DOI 10.1007/s10967-013-2626-4, 2013.

Target Plates

November 14, 2013


• TR19 have been demonstrated to ~240 µA to date

• ~200 µA average over 6 hour irradiation

• > 9Ci production

• PETtrace • Pressed & sintered pellets • Targets demonstrated to 100

µA to date

Production PETtrace (GBq/µA)

Yield (GBq) 6hrs @ 130 µA

TRPET (GBq/µA)

Yield 6hrs @ 300 µA

Celler 2.8 ± 0.3 182 (4.9 Ci) 3.8 ± 0.4 570 (15.4 Ci) Tárkányi 3.4 ± 0.3 221 (6.0 Ci) 4.4 ± 0.4 660 (17.8 Ci) Our Data (to date) 1.8 ± 0.2 117 (3.2 Ci) 3.5 ± 0.4 525 (14.2 Ci)

Tc requirement = 125 GBq (3.3 Ci) per day per 0.5M population

• F. Benard, K.R. Buckley, T.J. Ruth, S.K. Zeisler, J. Klug, V. Hanemaayer, M. Vuckovic, X. Hou, A. Celler, J.P. Appiah, J. Valiant, M.S. Kovacs, P. Schaffer, Implementation of multi-Curie production of 99mTc by conventional medical cyclotrons, Journal of Nuclear Medicine, Submitted October 2013.

• V. Hanemaayer, F. Bénard, K.R. Buckley, J. Klug, M. Kovacs, C. Leon, T.J. Ruth, P. Schaffer, S.K. Zeisler, Solid Targets for 99mTc Production on Small Medical Cyclotrons. Journal of Radioanalytical and Nuclear Chemistry, 2013, accepted, in press.

• T. J. Morley, L. Penner, P. Schaffer, T. J. Ruth, F. Bénard, E. Asselin, The deposition of smooth metallic molybdenum from aqueous electrolytes containing molybdate ions. Electrochemistry Communications, 2012, 15, 78-80.

• T. J. Morley, M. Dodd, K. Gagnon, V. Hanemaayer, J. Wilson, S. A. McQuarrie, W. English, T. J. Ruth, F. Bénard, P. Schaffer, An automated module for the separation and purification of cyclotron-produced 99mTcO4. Nuclear Medicine and Biology, 2012, 39, 551-559.

• K. Gagnon, F. Bénard, M. Kovacs, T.J. Ruth, P. Schaffer, J.S. Wilson and S.A. McQuarrie, Cyclotron production of 99mTc: Experimental measurement of the 100Mo(p,x)99Mo, 99mTc, and 99gTc excitation functions from 8 to 18 MeV. Nuclear Medicine and Biology 2011, 38, 907-916.

• J. Klug, K. Buckley, M. Dodd, C. Hoehr, P. Tsao, J.P. Appiah, C. Economou, P. Schaffer, S. Zeisler, A new transfer system for solid targets. American Institute of Physics Conference Proceedings, 2012, 1509, 146.

• T.J. Morley, C. Hoehr, K. Buckley, K. Gagnon, S. McQuarrie, M. Kovacs, P. Schaffer, F. Bénard, T.J. Ruth, Simple, rapid production of Tc-94m. Journal of Nuclear Medicine, 2011, 52, S290.

• T.J. Morley, C. Hoehr, K. Buckley, P. Schaffer, F. Bénard, T.J. Ruth, Rapid and efficient production of Tc-94m. Journal of Labelled Compounds and Radiopharmaceuticals. 2011, 51, S245.

• P. Schaffer, T.J. Morley, K. Gagnon, E. Asselin, K.R. Buckley, J. Klug, V. Hanemaayer, S. Zeisler, M. Dodd, S.A. McQuarrie, M.S. Kovacs, F.S. Prato, J.F. Valliant, F. Bénard, T.J. Ruth, TJ, Assessing the potential of using the 100Mo(p,2n)99mTc transformation as a means of producing Curie-quantities of 99mTc on existing cyclotron infrastructure. Journal of Labelled Compounds and Radiopharmaceuticals 2011, 54, S247-S247.

• P. Schaffer, K. Gagnon, T.J. Morley, D. Abrams, M.S. Kovacs, S.A. McQuarrie, S.K. Zeisler, F. Bénard, T.J. Ruth, Direct on-target production of Tc-99m using the Mo-100(p,2n)Tc-99m transformation, Nuclear Medicine and Biology, 2010, 37, 713-714.

• P. Schaffer, K. Gagnon, T.J. Morley, D. Abrams, J. Wilson, M.S. Kovacs, S.A. McQuarrie, E. Asselin, S.K. Zeisler, F. Bénard, T.J. Ruth, Direct On-Target Production of 99mTc using the 100Mo(p,2n)99mTc transformation, Technetium and Other Metals in Chemistry and Medicine, 2010, 8, 431-434.

• F. Bénard, S. Zeisler, K.-S. Lin, M. Vuckovic and P. Schaffer. Process for Separation of 99mTc as pertechnetate from molybdate, US Provisional Patent 61745379.

• K. Buckley, S. Zeisler, J. Klug, M. Dodd, V. Hanemaayer, F. Bénard, M. Kovacs, J. Valliant, P. Schaffer, Processes, Systems and Apparatus for Cyclotron Production of Technetium-99m, US Provisional Patent 61640610.

Knowledge Products

November 14, 2013


• Improve access to radiometals to facilitate development of imaging agents for specific biomarkers such as HER2 expression

• Stay within the liquid target paradigm yet provide Tc-94m, Sc-44, Ga-68, Y-86, Zr-89, Zn-63, Co-55, Mn-52, Cu-61, etc.

• Quantities sufficient for labelling and pre-clinical studies

• Targetry and separation process are simpler

Radiometals in Liquid Targets

November 14, 2013


Radiometals in Liquid Targets

November 14, 2013


TRIUMF Paul Schaffer (Co-PI), Conny Hoehr, Stefan Zeisler, Vicky Hanemaayer, Tom Ruth, Tom Morley, Chris Lee, Qing Miao, Hua Yang, Ken Buckley, Brian Badesso, Mike Adam, Elisabeth Oehlke, Simon Ferguson, Linda Graham, Dave Prevost

British Columbia Cancer Agency Francois Benard (PI), Gemma Dias, Julius Klug, Kuo-Shyan Lin, Wade English, Don Yapp, Milan Vuckovic

McGill William Muller

University of British Columbia

Anna Celler, Xinchi Hou, Eric Price, Chris Orvig, Mark Martinez, Pouyan Jahangiri

ACSI Erik Van Lier, Alexander Zyuzin, Elena Ranyuk, Jayden Sader, Ania Posacka

Legend: Student Post-doc Trained through TRIUMF

• “Conventional” Liquid target • Highly concentrated solutions needed

• For 94mTc production • (NH4)6Mo7O24 · H2O dissolved in H2O, H2O2 slowly added • Highest molybdenum concentration achieved

0.541 ± 0.003 g/mL • For 44Sc production

• Ca(NO3)2 · H2O dissolved in H2O • Highest calcium concentration achieved

0.180 g/mL

• This process stresses the equipment • Need to know fundamentals to design better target

Process

November 14, 2013


• 68Zn(p,n)68Ga

Stressing the system

November 14, 2013


HAVAR as received from manufacturer

Havar foil boiled in zinc nitrate 2.5 hours, ~120 ºC

Niobium foil boiled in zinc chloride 2.5 hours, ~120 ºC

Havar foil boiled in zinc chloride 2.5 hours, ~120 ºC

• Syphon target

Improving the system

November 14, 2013


Image courtesy of Matthew Stokely.

Hoehr et al., AIP Conference Proceedings 1509, 56, 2012.

Improving the system

November 14, 2013


• Manual loading system unreliable

• Automated loading system with purging function to prevent clogging (pinch valves)

• Run frequency increased from weekly to daily

• Reduced amount of loaded volume

Separation of 44Sc

November 14, 2013


0

10

20

30

40

50

1 2 3 4 544

Sc a

ctiv

ity (

%)

Fractions

Solution from target

12M HCl

4mL

4mL

Mixing vial

Resin (DGA 50 mg)

Waste 1 (8mL) Waste 2 (3mL) Possible 44Ca recovery

1. Adsorption of 44Sc

2. Wash of Column

1.

6M HCl (3 x 1mL)

2.

0.05M HCl

Elution (2.5 mL)

5 x 0.5mL

Elution profile in 0.5 mL fractions (n = 3)

N,N,N’,N’-tetra-n-octyldiglycolamide

44Sc activity: 2.4 ± 0.9 % (n = 5)

44Sc activity: 88.1 ± 6.2 % (n = 5)

1. J. E. Duval, M. H. Kurbatov, J. Am. Chem. Soc. 75 (9), p. 2246, 1953. . 2. G. W. Severin et al., Appl. Rad. Isot. 70, p. 1526, 2012. 3. S. Krajewski et al., Radiochim. Acta, 101 (5), p. 333, 2013. 4. M. Bunka et al., Annual Report 2011, Labor für Radio- und Umweltchemie der Universität Bern und des Paul Scherrer Instituts, p.59, 2011. 5. G. W. Severin et al., AIP Conference Proceedings 1509, p. 125, 2012.

• Separation of 44Sc • Filter paper 1 • 0.22 μm Millex-GV 13mm diameter

syringe filter 2 • Chelex 100 3 • DGA (N,N,N’,N’-tetra-n-

octyldiglycolamide) 4 • Other resins: hydroxamate,

carboxylate-functionalized resins 5

Radiolabelling with 44Sc

November 14, 2013


• Synergy with parallel effort - see Miao poster this afternoon

TAT-PNA1-KN3 (synthesized at TRIUMF)

OO O N

HNH

NO O

NHN

O

O

NH

NO O

NN

O

NH2

NH

NO O

NHN

O

O

NH

NO O

NN

O

NH2

NH

NO O

NN

O

NH2

NH

NO O

N

HN

NNH2N

O

NH

NO O

NHN

O

O

NH

NO O

NN

O

NH2

NH

NO O

N

HN

NNH2N

O

NH

NO O

NN

O

NH2

NH

NO O

NHN

O

O

NH

NO O

NN

O

NH2

NH

NO O

NHN

O

O

NH

NO O

NN

O

NH2

NH

NO O

NN

NH2

NN

ON3

HN

O

NH2NH2HN

NH

HN

O

NH2O

O HN

H2N NH

HN

NHO

H2N NH

NH

HN

O

H2N NH

HN

NHO

H2N NH

HN

NHO

NHO

H2 N

HNHO

O HN

O

NH2

H2N NH

HN

NHO

HN

O

cell-penetrating peptide Specific designed PNA sequence Handle for further modification

TAT-PNA1 + p-SCN-Bn-DOTA

TAT-PNA1 + p-SCN-Bn-DTPA + 44Sc

82% radiochemical yield, ~ 4 μCi, RT, 200 min, pH 4, 1 nmol ligand 90% radiochemical yield, ~ 4 μCi, 50ºC, 150 min, pH 4, 1 nmol ligand

• C. Hoehr, E. Oehlke, C.J. Lee, X. Hou, K. Buckley, V. Hanemaayer, S. Zeisler, T. Ruth, A. Celler, P. Schaffer, F. Benard, 44gSc production using a water target on a 13 MeV cyclotron, Nuclear Medicine and Biology, Accepted, October 2013.

• C. Hoehr, T. J. Morley, K. Buckley, M. Trinczek, V. Hanemaayer, P. Schaffer, T. J. Ruth, F. Bénard, Radiometals from liquid targets: 94mTc production using a standard water target on a 13 MeV cyclotron. Applied Radiation and Isotopes, 2012, 70, 2308-2312.

• C. Hoehr, B. Badesso, T. Morley, M. Trinczek, K. Buckley, S. Zeisler, V. Hanemaayer, T.J. Ruth, F. Bénard, P. Schaffer, Producing radiometals in liquid targets: proof of feasibility with Tc-94m. American Institute of Physics Conference Proceedings 2012,1509, 56.

• C Hoehr, E Oehlke, B Badesso, V Hanemaayer, S Zeisler, H Yang, K Buckley, TJ Ruth, F Bénard, P Schaffer, "A Simple Method for producing and purifying 44Sc from a liquid target using low energy medical cyclotrons", Society for Nuclear Medicine and Molecular Imaging, Vancouver, BC, Canada, June 9, 2013.

• Mentioned in Highlights Summary! • C. Hoehr, B. Badesso, T. Morley, M. Trinczek, K. Buckley, J. Klug, S. Zeisler, V.

Hanemaayer, T.R. Ruth, F. Benard, P. Schaffer, “Producing Radiometals In Liquid Targets: Proof Of Feasibility With 94mTc.” 14th International Workshop on Targetry and Target Chemistry. Cancun, Mexico, Aug. 26-29, 2012.

• C. Hoehr, T. Morley, M. Trinczek, V. Hanemaayer, P. Schaffer, T. Ruth, F. Bénard, “Radiometals from liquid targets for the production of PET isotopes.” Canadian Association of Physicists Conference, Calgary, AB, June 11-15, 2012.

Knowledge Products

November 14, 2013


radioisotope development - triumf · 2013-11-14 · radioisotope development . international peer...

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