Small Cyclotron Production of Ir and its Application to ......Isotope Production 0 10 20 30 40 50 60...

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Isotope Production 0 10 20 30 40 50 60 70 80 5 7 9 11 13 15 17 σ (mb) Energy (MeV) Hilgers 2005 Szelecsenyi 2010 Introduction Iridium Cyclometalate Chemistry • Cyclometalate Ir complexes have ideal photophysical properties, e.g., quantum yields, Stokes shifts, luminescence lifetimes [2] • Varying cyclometalating & ancillary ligands allow: • Tunable emission spectra • Control of charge & lipophilicity • Attachment of biological vectors Abstract Acknowledgment & Reference Target Development Small Cyclotron Production of 192 Ir and its Application to Nuclear Medicine Graeme Langille a , Paul Schaffer a,b , Tim Storr a , Corina Andreoiu a a Department of Chemistry, Simon Fraser University; b Department of Nuclear Medicine, TRIUMF Nuclear Medicine • Radiopharmaceuticals (RP) use various decay radiations to probe and treat disease states (Fig. 1) • The general structure of an RP contains: • Radioisotope: chosen by chemical/nuclear properties • Biological vector: interacts with tissue of interest • Radiometals offer chemical versatility Multifunctional Radiopharmacy • Combining therapy with molecular imaging (e.g. LCI) • Optical microscopy allows LCI <μm resolution • Compare: PET (mm), SPECT (cm), MRI (<mm) Figure 1: General principle of targeted radiopharmacy Figure 2: LCI image of cells treated with cyclometalated Ir compound appended to D-fructose molecule from [1] • Reactor produced 192 Ir used in brachytherapy t 1/2 = 73.8 d; EC = 5%, β - = 95%; E β = 0.7 MeV γ spectrum complex, unsuitable for imaging • Medical cyclotrons widespread, traditionally make PET isotopes ( 18 F, 11 C, 13 N); radiometal production growing 192 Os(p,n) 192 Ir cross section published at low p energy (Fig. 3) nat Os(p,x) reactions unpublished; opportunity for study Figure 3: Excitation function of the 192 Os(p,n) 192 Ir reaction [3,4] Iridium Cyclometalate Chemistry Os electroplating • Ag target plate backing chosen for low chemical and nuclear reactivity; modified from [5] • Os metal heated in HNO 3 ! OsO 4 (Fig. 4 A); added to electrolytic bath • 60 mA, 3 V, 1.75 hours, 70 o C, pH ~ 13; Ag target cathode, Pt wire anode, rapid stirring (Fig. 4 B, C) • 20 mg metallic Os deposited, ready for irradiation Proposed post-irradiation target processing Hot HCl will selectively dissolve Os (and Ir) off Ag foil • An anion exchange column equilibrated at 6M HCl will retain Os (OsCl 6 2- ) and elute Ir (IrCl 6 3- ) [6] • Neutralization of HCl will yield IrCl 3 · nH 2 O, a common precursor in cyclometalate chemistry Figure 4: A. Distillation of OsO 4 ; B. Electrochemical cell, housed in beaker; C. Os electroplated on Ag foil • Proposed test irradiation conditions: 5μA, 13 MeV, 5 hours TRIUMF TR13 medical cyclotron: 13 MeV protons Microwave Chemistry • Microwave speeds synthesis ~50x • Initial syntheses performed on non-radioactive Ir for optimization to carrier-free concentrations • Compounds of interest synthesized and isolated as references for ongoing characterization • Synthetic goals: water as solvent; single pot • Carrier-free concentrations to be isolated with high performance liquid chromatography Biological Targeting • Ancillary and cyclometalating ligands will be modified with targeting vectors (e.g. Fig. 6) 192 Ir t 1/2 suited to long biological t 1/2 , e.g. monoclonal antibodies; supported by kinetic stability of Ir cyclometalates Figure 5: Ir ligation with cyclometalating ligands and ancillary ligand. Compound 1 isolated in 39% yield; purification of 3 not yet complete. Compounds 2 & 4 offer higher quantum yields but not yet synthesized. Figure 6: Example synthesis of a click-compatible ancillary ligand, suitable for conjugation to a biological vector Research Goals N N HO OH Br N N O O NaH, DMF Ir N N N H O O OH N C C N " Demonstrate plating of Os on Ag " Perform non-radioactive iridium cyclometalate chemistry Develop radiotracer characterization method Obtain preliminary cross section data of unpublished nat Os(p,x) Demonstrate 1 st application of cyclometalation reaction to radio-Ir A B C Drs Tim Storr & Krzysztof Starosta (Advisory Committee) Dr Robert Young (SFU); Dr Stefan Zeisler (TRIUMF) • Funding: Ir Ir Cl Cl C C C C N N N N IrCl 3 *nH 2 O 2-ethoxy ethanol 30 m, Microwave + N C Ir Ir Cl Cl C C C C N N N N 2-ethoxy ethanol 15 m, MW L L + Ir N N C L L C = L L = N C Cl N N 1, 3 2, 4 N F F N 1, 2 3, 4 1. K. Lo et al. Metallomics 5 (2013) 808 2. K. Lo, K. Zhang. RSC Advances 2 (2012) 12 069 3. K. HIlgers, S. Sudar, S. Quaim. Appl Rad Isot 63 (2005) 93 4. F. Szelecsenyi et. al. Nucl Inst Meth Phys Res B 268 (2010) 3306 5. L. Greenspan. Electrodeposition of Osmium. Patent 3,622,474 (1971) 6. E. Campbell, F. Nelson. J Inorg Nucl Chem 3 (1956) 233 Objective: To demonstrate the first synthesis of an iridium radiopharmaceutical, from the medical cyclotron production of 192 Ir to its application to cyclometalate chemistry Why: Cyclometalate compounds have excellent photophysical properties useful in luminescence cell imaging (LCI), with applications in cancer diagnosis and research Strategy: Iridium isotopes will be generated via proton bombardment of an osmium target, then isolated and applied to a synthetic method currently under development Benefit: Radio-iridium cyclometalates would merge targeted cancer radiotherapy with sub-cellular LCI tracking

Transcript of Small Cyclotron Production of Ir and its Application to ......Isotope Production 0 10 20 30 40 50 60...

Page 1: Small Cyclotron Production of Ir and its Application to ......Isotope Production 0 10 20 30 40 50 60 70 80 5 7 9 11 13 15 17 19 σ) Energy (MeV) 192Os(p,n)192Ir Excitation Function

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192Os(p,n)192Ir Excitation Function

Hilgers 2005 Szelecsenyi 2010

Introduction

Iridium Cyclometalate Chemistry •  Cyclometalate Ir complexes have ideal photophysical properties, e.g., quantum yields, Stokes shifts, luminescence lifetimes [2]

•  Varying cyclometalating & ancillary ligands allow: •  Tunable emission spectra •  Control of charge & lipophilicity •  Attachment of biological vectors

Abstract

Acknowledgment & Reference

Target Development

Small Cyclotron Production of 192Ir and its Application to Nuclear Medicine

Graeme Langillea, Paul Schaffera,b, Tim Storra, Corina Andreoiua a Department of Chemistry, Simon Fraser University; b Department of Nuclear Medicine, TRIUMF

Nuclear Medicine •  Radiopharmaceuticals (RP) use various decay

radiations to probe and treat disease states (Fig. 1) •  The general structure of an RP contains:

•  Radioisotope: chosen by chemical/nuclear properties

•  Biological vector: interacts with tissue of interest •  Radiometals offer chemical versatility Multifunctional Radiopharmacy •  Combining therapy with molecular imaging (e.g. LCI) • Optical microscopy allows LCI <µm resolution

•  Compare: PET (mm), SPECT (cm), MRI (<mm)

Figure 1: General principle of targeted radiopharmacy

Figure 2: LCI image of cells treated with cyclometalated Ir compound appended to D-fructose molecule from [1]

•  Reactor produced 192Ir used in brachytherapy

•  t1/2 = 73.8 d; EC = 5%, β- = 95%; Eβ = 0.7 MeV •  γ spectrum complex, unsuitable for imaging

• Medical cyclotrons widespread, traditionally make PET isotopes (18F, 11C, 13N); radiometal production growing

•  192Os(p,n)192Ir cross section published at low p energy (Fig. 3) •  natOs(p,x) reactions unpublished; opportunity for study

Figure 3: Excitation function of the 192Os(p,n)192Ir reaction [3,4]

Iridium Cyclometalate Chemistry

Os electroplating •  Ag target plate backing chosen for low chemical and nuclear reactivity; modified from [5]

• Os metal heated in HNO3 ! OsO4 (Fig. 4 A); added to electrolytic bath

•  60 mA, 3 V, 1.75 hours, 70oC, pH ~ 13; Ag target cathode, Pt wire anode, rapid stirring (Fig. 4 B, C)

•  20 mg metallic Os deposited, ready for irradiation Proposed post-irradiation target processing •  Hot HCl will selectively dissolve Os (and Ir) off Ag foil •  An anion exchange column equilibrated at 6M HCl will retain Os (OsCl62-) and elute Ir (IrCl63-) [6]

•  Neutralization of HCl will yield IrCl3· nH2O, a common precursor in cyclometalate chemistry Figure 4: A. Distillation of OsO4; B. Electrochemical cell,

housed in beaker; C. Os electroplated on Ag foil

•  Proposed test irradiation conditions: 5µA, 13 MeV, 5 hours •  TRIUMF TR13 medical cyclotron: 13 MeV protons

Microwave Chemistry • Microwave speeds synthesis ~50x •  Initial syntheses performed on non-radioactive Ir for optimization to carrier-free concentrations

•  Compounds of interest synthesized and isolated as references for ongoing characterization

•  Synthetic goals: water as solvent; single pot •  Carrier-free concentrations to be isolated with high performance liquid chromatography

Biological Targeting •  Ancillary and cyclometalating ligands will be modified with targeting vectors (e.g. Fig. 6)

•  192Ir t1/2 suited to long biological t1/2, e.g. monoclonal antibodies; supported by kinetic stability of Ir cyclometalates

Figure 5: Ir ligation with cyclometalating ligands and ancillary ligand. Compound 1 isolated in 39% yield; purification of 3 not yet complete. Compounds 2 & 4 offer higher quantum yields but not yet synthesized.

Figure 6: Example synthesis of a click-compatible ancillary ligand, suitable for conjugation to a

biological vector

Research Goals

N N

HO OHBr

N N

OO

NaH, DMF

IrN

N

NH

O

OOH

NC

CN

" Demonstrate plating of Os on Ag " Perform non-radioactive iridium cyclometalate chemistry •  Develop radiotracer characterization method •  Obtain preliminary cross section data of unpublished natOs(p,x) •  Demonstrate 1st application of cyclometalation reaction to radio-Ir

A B

C

•  Drs Tim Storr & Krzysztof Starosta (Advisory Committee) •  Dr Robert Young (SFU); Dr Stefan Zeisler (TRIUMF) •  Funding:

Ir IrCl

Cl

CC

C C

N

N

N

N

IrCl3*nH2O2-ethoxy ethanol

30 m, Microwave+

N

C

Ir IrCl

Cl

CC

C C

N

N

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N

2-ethoxy ethanol

15 m, MWL

L+ Ir

N

NC L

LC

=L

L

=N

C

Cl

N N

1, 3 2, 4

N

F

F

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1.  K. Lo et al. Metallomics 5 (2013) 808 2.  K. Lo, K. Zhang. RSC Advances 2 (2012) 12 069 3.  K. HIlgers, S. Sudar, S. Quaim. Appl Rad Isot 63 (2005) 93 4.  F. Szelecsenyi et. al. Nucl Inst Meth Phys Res B 268 (2010) 3306 5.  L. Greenspan. Electrodeposition of Osmium. Patent 3,622,474 (1971) 6.  E. Campbell, F. Nelson. J Inorg Nucl Chem 3 (1956) 233

• Objective: To demonstrate the first synthesis of an iridium radiopharmaceutical, from the medical cyclotron production of 192Ir to its application to cyclometalate chemistry

• Why: Cyclometalate compounds have excellent photophysical properties useful in luminescence cell imaging (LCI), with applications in cancer diagnosis and research

•  Strategy: Iridium isotopes will be generated via proton bombardment of an osmium target, then isolated and applied to a synthetic method currently under development

•  Benefit: Radio-iridium cyclometalates would merge targeted cancer radiotherapy with sub-cellular LCI tracking