Introduction to Nuclear Medicine or Molecular Imaging

1
Introduction to Nuclear Medicine or Molecular
Imaging

• Paul Benny
• Department of Chemistry

2
History of Radiopharmacy

• Medicinal applications since the discovery of
  Radioactivity
• Early 1900s
• Limited understanding of Radioactivity and dose

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1912 George de Hevesy
Father of the radiotracer experiment. Used a
lead (Pb) radioisotope to prove the recycling of
meat by his landlady. Received the Nobel Prize
in chemistry in 1943 for his concept of
radiotracers
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Early use of radiotracers in medicine

• 1926 Hermann Blumgart, MD injected 1-6 mCi of
  Radium C to monitor blood flow (1st clinical
  use of a radiotracer)
• 1937 John Lawrence, MD used phosphorus-32
  (P-32) to treat leukemia (1st use of artificial
  radioactivity to treat patients)
• 1937 Technetium discovered by E. Segre and C.
  Perrier

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Early Uses continued

• 1939 Joe Hamilton, MD used radioiodine (I-131)
  for diagnosis
• 1939 Charles Pecher, MD used strontium-89
  (Sr-89) for treatment of bone metastases.
• 1946 Samuel Seidlin, MD used I-131 to
  completely cure all metastases associated with
  thyroid cancer. This was the first and remains
  the only true magic bullet.
• 1960 Powell Richards developed the Mo-99/Tc-99m
  generator
• 1963 Paul Harper, MD injected Tc-99m
  pertechnetate for human brain tumor imaging

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Part 1 Characteristics of a Radiopharmaceutical

• What is a radiopharmaceutical?
• A radioactive compound used for the diagnosis and
  therapeutic treatment of human diseases.

Radionuclide Pharmaceutical
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Radioactive Materials

• Unstable nuclides
• Combination of neutron and protons
• Emits particles and energy to become a more
  stable isotope

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Radiation decay emissions

• Alpha (a or 4He2)
• Beta (b- or e-)
• Positron (b)
• Gamma (g)
• Neutrons (n)

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Interactions of Emissions

• Alpha (a or 4He)
• High energy over short linear range
• Charged 2
• Beta (b- or e-)
• Various energy, random motion
• negative
• Gamma (g)
• No mass, hv

• Positron (b)
• Energy gt1022 MeV, random motion
• Anihilation (2 511 MeV 180)
• Negative
• Neutrons (n)
• No charge, light elements

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Half Life and Activity

• Radioactive decay is a statistical phenomenon
• t1/2
• l decay constant
• Activity
• The amount of radioactive material

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Why use radioactive materials anyway?

• Radiotracers
• High sensitivity
• Radioactive emission (no interferences)
• Nuclear decay process
• Independent reaction
• No external effect (chemical or biochemical)
• Active Agent
• Monitor ongoing processes

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Applications in Nuclear Medicine

• Imaging
• Gamma or positron emitting isotopes
• 99mTc, 111In, 18F, 11C, 64Cu
• Visualization of a biological process
• Cancer, myocardial perfusion agents
• Therapy
• Particle emitters
• Alpha, beta, conversion/auger electrons
• 188Re, 166Ho, 89Sr, 90Y, 212Bi, 225Ac, 131I
• Treatment of disease
• Cancer, restenosis, hyperthyroidism

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Ideal Characteristics of a Radiopharmaceutical

• Nuclear Properties
• Wide Availability
• Effective Half life (Radio and biological)
• High target to non target ratio
• Simple preparation
• Biological stability
• Cost

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Ideal Nuclear Properties for Imagining Agents

• Reasonable energy emissions.
• Radiation must be able to penetrate several
  layers of tissue.
• No particle emission (Gamma only)
• Isomeric transition, positron (b), electron
  capture
• High abundance or Yield
• Effective half life
• Cost

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Detection Energy Requirements

• Best images between 100-300 KeV
• Limitations
• Detectors (NaI)
• Personnel (shielding)
• Patient dose
• What else happens at higher energies?
• Lower photoelectric peak abundance, due to
  the Compton effect

Cs-137 decay (662 KeV)
Energy ?
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Gamma Isotopes

• Radionuclide T1/2 g ()
• Tc-99m 6.02 hr 140 KeV (89)
• Tl-201 73 hr 167 KeV (9.4)
• In-111 2.21 d 171(90), 245(94)
• Ga-67 78 hr 93 (40), 184 (20), 300(17)
• I-123 13.2 hr 159(83)
• I-131 8d 284(6), 364(81), 637(7)
• Xe-133 5.3 d 81(37)

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Positron Emission Tomography

• b slows to thermal energies two 511KeV gammas
  rays emitted approximately 180 to each other
• Coincidence detection
• b travel some distance from the initial site
• Cyclotron produced
• Sharp images
• Quantitative
• Short Half Lives

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PET Isotopes

• Nuclide T1/2 Production
• Carbon-11 20.4 min 10B(d,n)11C
• Nitrogen-13 9.96 min 12C(d,n)13N
• Oxygen-15 2.05 min 14N(d,n)15O
• 16O(p,pn)15O
• 12C(a,n)15O
• Fluorine-18 110 min 18O(p,n)18F
• Copper-64 12.7 hrs 64Ni(p,n)64Cu

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ImagingPET vs. SPECT

• More complex and larger molecules
• Less quantitative
• Longer half lives
• Available world wide
• Less expensive
• No special production equipment needed

• Biologically useful isotopes
• 11C, 13N, 15O, 18F
• More Quantitative (b)
• Very short T1/2
• Very expensive
• On site cyclotron

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Radiopharmaceuticals for Therapy

• Similar to imaging requirements
• Effective half life, high abundance, availability
  etc.
• Particle emitters
• a, b, auger, amd conversion electrons
• Particle energy
• Is higher better? Linear Energy Transfer (LET)
• Additional g rays help with determining
  localization via imaging methods.

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Some Radionuclides for Therapy

• Radionuclide T1/2 Particle (MeV)
• Re-186 3.8 b- (1.07)
• Re-188 17 hrs b- (2)
• I-131 8 d b- (2)
• P-32 14.3 d b- (1.7)
• Sr-89 50.6 d b- (1.43)
• Sm-153 1.9 d b- (0.81)
• Bi-212 1 hr a (6.051)

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Therapeutic Radiation Dose

• External cell receptors vs. DNA binding agents
• Distance does matter
• Ionization and angle of interaction
• Probability of DNA damage increases as distance
  decreases

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DNA Damage in Radiotherapy

• Ionization
• Direct and Indirect
• Alpha, beta, Auger electron, internal conversion
• Free Radical Induction
• (R., OH., HOO.)
• Irreparable damage to DNA through strand cleavage
• Double and single strand breaks
• Base pair mutation
• Therapy Goal Induce cellular apoptosis

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How do you prepare radioisotopes?

• Site produced
• Reactor or cyclotron
• Limited by half life, facilities,
• Limited Shipping distance
• Generator system
• Portable system
• Reusable

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Cyclotron
Reactor
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Production of Radionuclides
WSU Reactor

• Nuclear Reactor (neutrons)
• Fission of U-235
• Produces neutron rich radioisotopes
• Alpha, Beta, gamma decay
• (n, g) reaction
• Cyclotron (charged particles)
• Proton rich
• Positron, electron capture
• (p,n), (d,n) reaction
• most common

Washington University St. Louis, MO
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A generator facilitates the separation of two
radionuclides (parent and daughter) from each
other to yield a useable radioisotope (daughter)
for nuclear medicine studies.

• Transient equilibrium
• T1/2 daughter is less than 10 half lives than the
  parent
• Ad ld Ap e-lpt/(ld-lp)
• Secular equilibrium
• T1/2 of the parent much greater than 10 half
  lives of the daughter.
• Activity at equilibrium (Ap Ad)
• Cs-137 (T1/2 30 y) and Ba-137m (T1/2 2.5 min)

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Ideal Characteristics for a Generator

• Utilizes chemical characteristics of the parent
  and the daughter radionuclide.
• Output sterile and pyrogen free
• Biological pH
• Low radiation dose (Shielding)
• Inexpensive.
• Easy to produce.
• Simple elution method
• Reasonable half life of parent and daughter

Parent Daughter
Daughter
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99mTc The workhorse of Nuclear Medicine Industry

• Imaging Radionuclide
• gt90 FDA approve imagining agents are 99mTc
• Versatile chemistry
• Ideal Nuclear characteristics
• T1/2 6.02 hr
• Gamma, 140 KeV (89)
• Internal conversion (11)
• Energy vs. effectiveness of the decay
• Availability (generator)
• 99Mo?99mTc

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Mallinckrodt/Tyco 99mTc Generator

• High specific activity 99Mo from 235U fission
• Solid phase
• Alumina
• Liquid phase
• 0.9 saline
• Generator easy to use
• Reliable separation

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Common radiochemical generators

• Eluants
• 1. 0.9 NaCl
• (99Mo ? 99mTc)
• (82Sr ? 82Rb)
• 2. 0.05 N HCl
• (113Sn ? 113mIn)
• 3. O2 (81Rb ? 81mKr)
• 4. 1 N HCl 68Ge ? 68Ga)

• Column Materials
• 1. Alumina (99Mo ? 99mTc)
• Zirconia
• (113Sn ? 113mIn)
• Cation exchange resin
• (81Rb ? 81mKr)
• 4. Anion exchange resin
• (62Zn ? 62Cu)
• Stannic Oxide
• (82Sr ? 82Rb)

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Effective Half life (Radio and biological)

• Nuclear Decay (T1/2)
• Inherent statistical decay of the nuclide
• Biological T1/2
• Uptake/washout of the radiopharmaceutical
• Equilibration
• Decomposition
• Pairing of biological and radionuclidic half
  lives is imperative to optimize effectiveness of
  the drug.

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High target to non target ratio

• Lower activity require for detector statistics
  and visualization of target tissue.
• Low dose to non target tissues
• Bone Marrow, gastro intestine
• Decreased probability of organ overlap

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How do agents localize at target tissues?

• Method of Localization
• Active transport
• Phagocytosis (Liver uptake)
• Capillary blockade
• Simple/Exchange diffusion
• Compartmental Localization
• Chemisorption
• Antigen/Antibody reaction

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Several Types of Radiopharmaceuticals
Cocaine

• 1) Radioactive atom
• 131I- ,201Tl, 81mKr
• 2) Radioactive compound
• I, C, or transition metals.
• Covalent or coordination bond.

Ritalin
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Methods of Labeling

• Direct labeling
• Non specific binding
• Antibodies, red blood cells
• Site specific
• Iodination (Tyr) , Methylation (amine, cys)
• Chelate
• Metal Ligand coordination complex
• Bifunctional Chelate
• Normal chelate with biological targeting agent

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Chelate Groups

• Mixture of coordination donor atoms
• N, O, S, P, etc.
• Geared to metal and oxidation state
• Monodentate to multi-dentate
• 1-8 coordination donors
• Variety of coordination modes
• Fac, mer, planar, equatorial, tetrahedral,
  asymmetric

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Example Chelate Systems

• Various denticity (1-8)
• Variations of donor atoms (N,S,O,P)
• Metal chelate ring size
• Complex stability
• Combination of multiple ligands
• 22, 31,32

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Biological Target Design
Targeting Agent
Radionuclide
Biological Target

• Target a specific biological function

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Target Specific Radiopharmaceuticals
Biological target

• Targets (unique features)
• Cell surface receptors
• Transport mechanisms
• Proteins
• DNA/RNA

• Targeting Molecules
• Peptides
• Peptide mimics
• Nucleotides
• Small molecules
• Antibodies

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Types of Radiopharmaceuticals

• Small molecule
• Fast circulation
• Good specificity
• Less than 1,000 daltons
• Metal chelate considerable of mass
• Large molecule
• Slow circulation
• Excellent specificity
• Usually contains a biologically active motif
• Antibodies or fragments, B-12
• Metal chelate insignificant of mass

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Peptide Labeling

• Small peptides for specific receptors
• Easy to produce
• Greater number of variations to optimize the
  system
• Faster circulation through the body
• Maintains specificity.
• Better clearance
• Via kidneys rather than liver

Somatostatin
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Labeling Antibodies

• High specificity to an antigen or binding site
• Large molecular weight
• 50,000 daltons
• Labeling
• Direct non specific method (131I)
• Bifunctional chelate
• Mab fragments
• (F(ab)2, Fab)
• Similar immune response to Mab

Mab
F(ab)2
Fab