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5/10/2018 Radio Pharmacy - slidepdf.com
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Introduction to
Radiopharmacy & Nuclear Medicine
or Molecular Imaging
Muh Yanis MusdjaDepartment of Radiopharmacy
BATAN Indonesia
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History of Radiopharmacy
Medicinal applications since the discovery of Radioactivity
Early 1900’s 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 inchemistry 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 radioactivityto 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) fortreatment of bone metastases.
1946: Samuel Seidlin, MD used I-131 to completely cureall metastases associated with thyroid cancer. This was thefirst 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 forhuman brain tumor imaging
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What is a radiopharmaceutical?
A radioactive compound used for thediagnosis and therapeutic treatment of human diseases.
Radionuclide + Pharmaceutical
Part 1: Characteristics of a
Radiopharmaceutical
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Radioactive Materials
Unstable nuclides
Combination of neutron and protons
Emits particles and energy to become a morestable isotope
N →
↑
Z
Chart of the Nuclides
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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 or4
He) 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 >1022 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 astatisticalphenomenon
t1/2
l= decay constant
Activity
The amount of radioactive material
l
693.0=
t
el -
= *AA o
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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
99m Tc, 111In, 18F, 11C, 64Cu
Visualization of a biological process
Cancer, myocardial perfusion agents
Therapy
Particle emitters
Alpha, beta, conversion/auger electrons
188Re, 166Ho, 89Sr, 90 Y, 212Bi, 225 Ac, 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 higherenergies?
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 energiestwo 511KeV gammas raysemitted approximately 180° to each other
Coincidence detection
b+ travel some distance fromthe 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)15O12C(a,n)15O
Fluorine-18 110 min 18O(p,n)18F
Copper-64 12.7 hrs 64Ni(p,n)64Cu
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Imaging:
PET vs. SPECT
Biologically usefulisotopes
11C, 13N, 15O, 18F
More Quantitative ( b+ )
Very short T1/2
Very expensive
On site cyclotron
More complex andlarger molecules
Less quantitative
Longer half lives
Available world wide
Less expensive
No special productionequipment needed
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Radiopharmaceuticals for Therapy
Similar to imaging requirements Effective half life, high abundance, availability etc.
Particle emittersa, 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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N →
↑
Z
Chart of the Nuclides
Reactor
Cyclotron
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Production of Radionuclides
Nuclear Reactor (neutrons) Fission of U-235
Produces neutron richradioisotopes
Alpha, Beta, gamma decay (n, g ) reaction
Cyclotron (charged particles) Proton rich Positron, electron capture
(p,n), (d,n) reaction
most common
WSU Reactor
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 greaterthan 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 daughterradionuclide.
Output sterile and pyrogen free
Biological pH
Low radiation dose (Shielding)
Inexpensive.
Easy to produce.
Simple elution method
Reasonable half life of parent anddaughter
Radionuclide
Mixture
Column
Material
Desired Radionuclide
Eluant
Parent+
Daughter
Daughter
99mT “Th kh f N l M di i
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99m Tc “The workhorse of Nuclear Medicine
Industry”
Imaging Radionuclide
>90% FDA approve imagining agents are 99m Tc
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→99m Tc
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Mallinckrodt/Tyco 99m Tc 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
Column Materials
1. Alumina (99Mo 99m Tc)
2. Zirconia(113Sn 113mIn)
3. Cation exchange resin(81Rb 81mKr)
4. Anion exchange resin(62Zn 62Cu)
5. Stannic Oxide(82Sr 82Rb)
Eluants
1. 0.9% NaCl(99Mo 99m Tc)
(82Sr 82Rb)
2. 0.05 N HCl(113Sn 113mIn)
3. O2 (81Rb 81mKr)
4. 1 N HCl 68Ge 68Ga)
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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 statisticsand 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
S l T f R di h i l
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Several Types of Radiopharmaceuticals
1) Radioactive atom131I- ,201 Tl+, 81mKr
2) Radioactive compound I, C, or transition metals.
Covalent or coordination bond.
Radionuclide Chelate
+
Radioactive Comlex
I
N
O
O
H3C O
O
O
HN
O
H3C
Cocaine
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
Non specific
Chelate
Bifunctional Chelate
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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
E l Ch l S
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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 2+2, 3+1,3+2
SH
NH HN
HN
O
O
O
OH
O
MAG3
NH HN
N N
OH OH
HMPAO
N N
OOH
OH
O
OH
O
DTPA
N
HO
O
HO
O
N N
O
OH
OH
O
OH
O
HO
O
EDTA
P
P
EtO
EtO
EtO OEt
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Biological Target Design
Target a specific biological function
Biological TargetRadionuclide
Targeting Agent
T S ifi
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Target Specific
Radiopharmaceuticals
Linker
TargetingMolecule
Radionuclide
BifunctionalChelate
Biological target
Targeting Molecules:
• Peptides• Peptide mimics
• Nucleotides
• Small molecules
• Antibodies
Targets (unique features)
• Cell surface receptors
• Transport
mechanisms
• Proteins
• DNA/RNA
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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 specificreceptors
Easy to produce
Greater number of variations tooptimize the system
Faster circulation through thebody
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 toMab
Mab
F(ab’)2 Fab