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Chem 2601/2011
Molecular Imaging
Lecture 3 and 4: Introduction to Nuclear imaging and Radiochemistry
Overview (lecture 3 and 4): 1) 2) 3) 4) 5) 6) The principles of Nuclear imaging Nuclear imaging techniques Instrumentation Introduction to radioactivity Production of radionuclides Radiochemistry
O F
OH
Nuclear Imaging techniques: 1) Positron emission tomography (PET) 2) Single Photon Emission Computed Tomography (SPECT) 3) Autoradiography
Positron
Electron
- Positron: the antimatter equivalent of an electron - Positrons are emitted from certain radioactive substances - Positrons and electrons annihilates to produce two gamma rays
- A chemical is labelled with a radioactive isotope (positron emitter) - Positrons annihilate in surrounding tissue - The resulting gamma rays are emitted from the subject
Autoradiography (imaging in vitro): Contact exposure of radioactive samples (e.g. 20 m tissue section on X-ray film) Lower resolution than fluorescence microscopy, but quantitative Requires low energy beta emission
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detector 1
coincidence window
detector 2
time (ns)
SPECT 12-15mm 0.03% yes Gamma emitters half-life > 6 hours 10-13 molar
Cost
$$
$$$ (5002000/scan)
Radioactivity: 1) 2) 3) 4) 5) Introduction to radioactivity Ionizing radiation Half-life and radioactive decay Specific activity Attenuation
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What is radioactivity?
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1897: Marie Curie named the rays radioactivity 1898: Marie and Pierre Curie discovered Polonium and Radium
Definitions: A nuclide (from nucleus) is an atomic species characterized by the specific constitution of its nucleus, i.e., by its number of protons Z and its number of neutrons N. A radionuclide is any radioactive nuclide. Isotopes are atoms from the same element (i.e. same proton number) but different number of neutrons.
Mass number = N + Z Proton (Z) number
18F-
Charge
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Radioactivity is defined as the process in which unstable atomic nuclei spontaneously emit ionizing radiation
E = mc2
Alpha particles = He nucleus Positrons = antimatter of electrons
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t1/2 = ln 2 /
At = A0 x e t
Where A0 is the activity at time zero and e = natural constant (2.718)
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Question: Carbon-11 has a half-life of 20 min. The synthesis of a tracer takes 40 min and it takes another 20 min to analyse the product before injection to a subject. The radiochemical yield is 20%. How much of the initial activity is available for injection?
Specific activity: Activity / Mass = Bq / mol Direct correlation between half-life and maximum specific activity: t1/2 = ln 2 / is the probability of radioactive decay: Low = long t1/2 High = short t1/2
The shorter the half-life the higher the maximum specific activity
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Specific activity important terms: Samples exclusively made up of molecules containing the radioactive nuclide are carrier-free (c.f.). Samples without addition of non-radioactive carrier but containing naturally occurring isotopic dilutions are non-carrier-added (n.c.a.). Samples diluted with non-labelled molecules are carrier-added (c.a.).
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http://en.wikibooks.org/wiki/Basic_Physics_of_Nuclear_Medicine/Attenuation_of_Gamma-Rays 30
Nuclear imaging is quantitative, because: Radioactive decay is determined by the half-life Radioactive decay is unaffected by the environment The interactions of ionizing radiation with matter follows clear physical rules and can be accounted for
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Question: What would happen if a subject is injected with a PET tracer but scanned with SPECT camera? What would happen if a subject is injected with a SPECT tracer but scanned with PET camera?
Radiochemistry: 1) 2) 3) 4) 5) Production of radionuclides Labelling with 11C Labelling with 18F Labelling with 123I Labelling with 3H
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Radiochemistry and production of radionuclides Examples for PET: 11C (t1/2 20.4 min) and 18F (t1/2 110 min) Example for SPECT: 123I (t1/2 13.1 h) Example for autoradiography: 3H (t1/2 12 years)
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10 min 20 min 2 min 110 min 13.1 h 6.01 h 68 min 1.26 min
124Te(p,2n)
+n
4He
All radionuclides for biomedical research are either produced by a cyclotron, or in nuclear reactors (directly or indirectly).
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Radiochemistry general principles: Fast reactions High yields Reliable and reproducible reactions Few side products Simple purification Introduce the radionuclide as late in the synthesis as possible!
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Radiochemical yield - example: Carbon-11 has a half-life of 20 min. You start the synthesis with 2 GBq of 11CO2. After 40 min you obtain 200 MBq of a tracer. The non-decay corrected radiochemical yield is: 0.2 GBq/2 GBq = 10% The decay-corrected radiochemical yield is: Decay correction: 0.2 GBq/(0.5 x 0.5) = 0.8 GBq 0.8 GBq/2 GBq = 40%
H4
H3I
11C
(p,)
11C
O2
11C
11C
O2
RMgX , SOCl2 (Grignard reagents) R11C (O)Cl RNH2 (amines) R11C (O)NHR
RNH2 (amines)
11C
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11C
H3I
H311CS OH
Base
H2N
C O
[11C ]Methionine
O2
O C
OMgBr
SOCl2
O C
Cl
RNHR
N
H3C
O N
C O
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Radiochemistry: labelling with fluorine-18 Advantages: Near ideal half-life (110 min) and low positron energy Small size makes it suitable for labelling of small molecules Fluoride can reduce metabolism of tracers Tracers can be transported for imaging at centres without a cyclotron Disadvantages: Limited reactivity, need to protect OH and NH groups! Limited chemistry fluoride is the most electronegative of all elements
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18F
[18F]FDG:
18F-
HCl (aq)
OAc
HO HO
OH O
OH
18
[18F]FDG
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O2N
18FO DMBn
Protecting group
O
N N O O
Deprotection
HO O
18
NH N O
DMTrO
Protecting group
18
38% RCY
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H N O
OMe OMe H N
O S
O R O
18
F
O
H3C
[18F]Fallypride
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O S O R
[18F]Fluoride
fluoroalkylation
H3C
OTs
18
ONH2 HO
O18
F
O
NH2
[18F]FET (fluoroethyltyrosine)
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Radiochemistry: labelling with iodine (123,124,125,131I) Advantages: Easy labelling chemistry Many isotopes available (autoradiography, SPECT and PET) Range of half-lives from 13 h to 60 days Disadvantages: Limited metabolic stability Large size (similar to benzene!) Limited labelling chemistry
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123I-
Oxidant
123
I NHR
123I+
O
HN HO
NHR
R O
HN HO
R O
Tyrosine residue
Advantages: High yields Simple chemistry Disadvantages: Low metabolic stability No control of labelling positions (in large proteins)
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I OH
H N OMe O
I , H2O2
H N
[123I]IBZM
Advantages: Site specific labelling Good yields Disadvantages: Only suitable for small molecules (or indirect labelling)
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T2, Pd/C
Alkylation with C3H3I equivalent to 11C H3I and suitable for the same reactions! Maximum specific activity for labelling with 3H ~ 2-3 GBq/mol
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Nuclear imaging strengths and weaknesses: + Excellent sensitivity (picomolar range ) + Deep tissue penetration + Allows absolute quantification - Limited resolution (time and space) - Expensive - Involves ionizing radiation
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SPECT
- Gamma emitters - Longer half-life (123I) > 6 h - Detects gammas emitted directly - Collimators for location - Can use multiple radionuclides - Lower resolution - Lower cost
Synopsis: autoradiography
Detects beta particles by X-ray film. Suitable radionuclides have long halflives 2 weeks to many years! The best results are achieved with low energy beta emitters, as energetic particles are not fully stopped by the imaging medium.
Synopsis: Radioactivity
Radioactive decay: -There main modes of decay are: alpha, beta, positron and gamma emission - Radioactivity is measured in Bq = 1 disintegration per second - Activity is defined by the half-life and the number of a radionuclide - Specific Activity is the activity per mass (in Bq / mol) Interactions of ionizing radiation with matter: -Each type of radiation interacts with matter in a unique way - Particles are rapidly stopped by matter and travel only short distances - Attenuation of gamma rays depends strongly on the gamma energy and atomic number of the absorbing matter NB: Radioactivity can readily be quantified as the activity level is unaffected by the environment and the interactions of ionizing radiation with matter can be accounted for.
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Synopsis: Radiochemistry
Production of radionuclides: Most PET radionuclides are produced with particle bombardment in a cyclotron Some radionuclides are produced in high flux nuclear reactors Radiochemistry: Reactions should be fast, efficient and reliable Radionuclides typically introduced late in the synthesis Chemistry of carbon-11, fluorine-18, iodine-123 and tritium Carbon-11 converted to CH3I or CO2 Carbon-11 labelling typically with methylation or Grignard reactions Fluorine-18 typically introduced by Sn2 nucleophilic reactions Iodine-123 introduced by addition to tyrosine or reaction with trialkytin groups Tritium typically introduced by reduction of unsaturated bonds
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Learning outcomes - you should understand: - The principles of radioactivity - The decay modes - The interaction of radiation with matter - The principles for imaging with PET, SPECT and autoradiography - How the decay mode, half-life and energy range of the radiation effect the suitability for imaging -The advantages and disadvantages of nuclear imaging - The chemistry of common radionuclides for PET, SPECT and autoradiography
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Assessment you should be able to apply your knowledge of radioactivity and nuclear imaging to explain underlying principles, solve practical problems and provide rationale explanations related to: - The principles of radioactivity - The decay modes - The interaction of radiation with matter - The principles for imaging with PET, SPECT and autoradiography - How the decay mode, half-life and energy range of the radiation effect the suitability for imaging -The advantages and disadvantages of nuclear imaging - Labelling reactions with common radionuclides for PET, SPECT and autoradiography
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