SPECTPET Isotopes: Production and Automation

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SPECT/PET Isotopes Production and Automation

• Mike Kovacs, Ph.D.
• Assistant Professor
• Diagnostic Radiology and Nuclear Medicine
• Dept of Chemistry
• mkovacs_at_lawsonimaging.ca x61096

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Learning Objectives

• Important characteristics of a radionuclide to be
  used in imaging.
• Methods used to produce the radionuclides used in
  imaging.
• How radiochemistry can be applied to the problem
  of radiopharmaceutical production.

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Radionuclides used inNuclear Medicine
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Radionuclide Considerations

• Type and energy of emissions
• Half-life
• Specific activity
• Radionuclidic purity
• Chemical properties
• Economics

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Type and Energy of Emissions

• Short range particles increase radiation dose to
  patient and do not contribute to image quality
  (?, ?, Auger e- in diagnostics)
• Ideally emit one photon, one energy
• 50-600 keV photon range ideal
• 150 keV photons ideal for SPECT cameras
• PET cameras specially designed for 511 keV photons

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Half-Life

• Ideally in the range of seconds to days
• Extremely short-lived radionuclides preclude
  preparation of complex radiopharmaceuticals
• Long-lived isotopes contribute to the patient
  dose
• Emission occurs largely outside the timeframe of
  the imaging procedure

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Specific Activity

• Requirement that a tracer not perturb the
  biological system under study
• Must not induce a pharmacologic or toxic response
• Importance can depend on the specific
  radiopharmaceutical and its mechanism of action
• E.g. 18FFDG low S.A.
• Monoclonal antibody high S.A.
• Toxic radiopharmaceutical high S.A.

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Radionuclidic Purity

• Fraction of radioactivity in sample attributed to
  the desired radionuclide
• Radioactivity/unit mass (or moles)
• Impurities can increase dose to patient
• Particulate radiation, long t1/2 etc.
• Can cause complications for detection of the
  desired photon energy
• E.g. increase of detector dead time
• 123I in the past containing 124I

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Chemical Properties

• Ease of radiolabeling and compounding of
  radiopharmaceuticals
• Effect on biochemical properties of known,
  similar compounds
• E.g. 11C substitute for natural 12C/13C
• 99mTc not found in nature
• Non-natural elements can be introduced as small
  molecules or chelated to make tagged analogues
  of biomolecules

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Economics

• Radionuclides may be difficult and expensive to
  prepare
• Rare and exotic starting materials
• Poor radionuclidic purity or difficult
  radiochemical separation
• Poor nuclear reactions low yield (fission,
  neutron activation, proton activation, etc)
• Low economic demand

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Production of Radionuclides

• Nuclear reactors
• Fission products and neutron reactions
• Accelerators (cyclotrons)
• Generators

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Fissionable Radionuclides

• Reactors and targets designed with various levels
  of 235U enrichment
• 239Pu can be chemically isolated avoiding costly
  isotopic enrichment

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99Mo
131I
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Nuclear Reactors

• Uranium fuel
• Jacketed in a heat and corrosion resistant
  coating (usually zirconium metal)
• Moderator
• to slow the high speed neutrons to energies
  suitable for fission and neutron reactions
• Control rods
• Neutron absorbing material to control neutron flux

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Nuclear Reactions

• Fission fragments
• E.g. 236U ? 99Y 134I 3n
• 99Y ? 99Zr ? 99Nb ? 99Mo (T1/2 in seconds)
• Neutron activation
• E.g. 31P (n,?) 32P 14N (n,p) 14C
• Rate of activation depends on energy, intensity
  of the flux, cross section

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Reactor-Produced Radionuclides of Interest in
Nuclear Medicine

• Fission fragments
• 99Mo (medium SA), 131I (medium SA)
• Neutron activation
• 124Xe (n,?) 125Xe? 125I (high SA)
• 130Te (n,?) 131Te? 131I (high SA)
• 98Mo (n,?) 99Mo (low SA)

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Accelerators - Cyclotrons

• Can accelerate electrically charged particles
• E.g. H, D, ?2, 3He2
• Particle energies much higher than neutron
  activation (10s of MeV)
• Most reactions change proton number ? high SA in
  general
• Produce neutron deficient radionuclides
• E.C. and ? decay common

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Cyclotron Reactions
14N (p,?) 11C 14N (d,n) 15O 18O (p,n) 18F 20Ne
(d,?) 18F 68Zn (p,2n) 67Ga 112Cd (p,2n)
111In 124Xe (p,2n) 123Cs ? 123Xe ? 123I 203Tl
(p,3n) 201Pb (separated) ? 201Tl
16O (3He,n) 18F - exotic
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F-18 Water Target
Helium
18O (p,n) 18F H218O ? H18F
H Beam
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Target Design Criteria

• Materials chemically inert, not activated by
  the beam, resistant to radiation damage
• 18O Water Economy - 220 per gram 95 (now 50)
• Heat Dissipation 50uA H beam at 18MeV is 1kW
  of power
• Window Design must be as thin as possible, yet
  withstand 500-800psi of pressure

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Generators

• Utilize a parent/daughter relationship where
  T1/2p gtgt T1/2d
• E.g. 99Mo/99mTc, 82Sr/82Rb, 68Ge/68Ga
• Very useful because they are a portable source of
  short-lived radionuclides

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99MoO42- bound on Al2O3 99mTcO4- elutes with
saline
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99mTc Generator Notes

• 99Mo available as fission product (medium S.A.)
  or (n,?) on natural 23.8 98Mo
• Former method 99Mo of choice
• Lower mass of 99Mo on Al2O3 minimized break
  through issues
• Less Al2O3 required? lower saline elution volumes
• Check for breakthrough 99Mo (740-780keV ?s) with
  3mm lead shield in dose calibrator

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82Rb Generator

• 82Sr2 (t1/225 days) prepared in cyclotron,
  loaded onto a cation exchange column
• Decays to 82Rb (t1/21.25 min)
• Excellent cardiac perfusion, PET
  radiopharmaceutical

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PET Radiochemistry

• Nucleophillic substitution 18F
• Electrophillic substitution 18F, 123/124/131I
• Methylation 11C
• Metal Chelation 68Ga, 111In, 64Cu

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SN2 Nucleophillic Substitution

• SN2 reaction
• Via 5-bond transition state
• Inversion of configuration
• F- is an extremely poor nucleophile
• ? Requires an excellent leaving group

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Helping Fluoride to React
K-K222F-
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18F Nucleophillic Synthesizer
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18F-FDG Chemistry The Hamacher Synthesis
Glycolysis glucose?pyruvate
FDG enters glycolytic pathway, stops at 1st
step, FDG-6-phosphate

• F- is a very poor nucleophile
• Acetonitrile must be dry
• Mannose triflate must be properly prepared
• Temperature control critical
• Acid hydrolysis
• Easy, Sep-Pak purification

K. Hamacher, H.H. Coenen, and G. Stöcklin, J.
Nucl. Med., 1986, 27, 235.
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F-MISO Hypoxia Agent
Hypoxic Conditions
Normoxic Conditions
J. Lim and J.-L. Berridge, Appl. Radiat. Isot.
1993, 44, 1085-91.
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FLT Fluoro-L-Thymidine
Chiral Carbon

• Imaging Mechanism
• Uptake a measure of cellular proliferation
• FLT phosphorylated and trapped
• Undergoes no further reactions

• Nucleophillic ring-opening substitution
• Semi-prep HPLC purification required

A. Blocher, C. Bieg, W. Ehrlichmann, B.M. Dohmen,
H.J. Machulla, J. Nucl. Med., 2001, 42, 257P.
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Electrophillic Substitution
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F-DOPA Synthesis
PROBLEM NON-REGIOSELECTIVE
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Regioselective F-DOPA Synthesis

• Regioselective by fluorodestannylation reaction
• Deprotection with HBr
• Only one product obtained
• Yields slightly lower than optimized
  non-regioselective reaction

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Iodination Reactions

• 2I- ? I2 via oxidation to form electrophile
• Regioselective iododestannylation reaction

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Methylation 11CCH3I Synthesis

• Wet and dry methods
• 11CCO2 feedstock from cyclotron
• Differences in specific activity and yield
• Commercially available synthesizers available

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Raclopride Synthesis

• Dopamine D2 receptor antagonist
• Subsequently purified by HPLC
• Preparation time lt30min

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Carfentanil Synthesis

• Potent opioid, 1000x potency of morphine
• 1 ?g will show activity in humans
• 11C imaging compounds often derived from known
  and highly potent drugs e.g. cocaine,
  tubocurare
• 100 homologous to cold analogues

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Metal Chelation

• Octreotide cyclic 8 a.a. somatostatin analogue
• Chelate DOTA introduced to complex a metal ion
• Metal-chelate complex must be stable, resistant
  to de-metallation, easily labelled
• Flexible approach often allows introduction of
  various metallic radionuclides e.g. 64Cu, 68Ge,
  111In