small cyclotron production of ir and its application to ......isotope production 0 10 20 30 40 50 60...
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Isotope Production
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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• 192Os(p,n)192Ir cross section published at low p energy (Fig. 3) • natOs(p,x) reactions unpublished; opportunity for study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
N
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
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 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