Introduction to Molecular Imaging

• Radionuclide : emits gamma radiation
• Pharmaceutical : physical/chemical component to which the radionuclide is attached to.

It is the pharmaceutical that largely determines the physiological behavior of the radiopharmaceutical and, therefore, the nature of the image obtained.

Definitions

• Activity The method to measure quantity of radioactivity = decay rate = number of nuclei which will disintegrate per second.
• Unit= Becquerel (Bq) = 1 disintegration / sec (very low activity).
• Old unit : curie (Ci) : 1mCi = 37 MBq
• Counts = number of β or γ rays registered by a detector
• The count rate = number of counts per second, cps
• Count rate is measured by a detector is less than the activity because the greater proportion of the rays usually miss the detector "undetected".
• However, Count rate α activity α number / mass of radioactive atoms in sample
• The fundamental law of radioactive decay (Exponential Law):

The activity of a radioactive sample decreases by equal fractions (%) in equal time intervals.

• Activity will never fall to zero

Physical Half-Life

The half-life (t 1/2) of a radionuclide

= the time taken for its activity to decay to 1/2 of its original value.

Exponential Decay

• Activity of a radioactive sample never falls to Zero.
• The graph of activity versus time → exponential curve
• If the activity is plotted on a logarithmic scale → straight-line

• Such graphs are useful in calculating:

1. Activity of prepared sample at a particular time

2. Time necessary to store radionuclide waste

Effective Half-Life

Rate at which the activity of radiopharmaceutical agent is eliminated from the body

Elimination of:

• Radionuclide by decays → (physical half‐life)
• Pharmaceutical by metabolic turnover & excretion → (biological half‐life)
• Activity of radiopharmaceutical administered by simultaneous effects of radioactive decay, metabolic turnover and excretion → (effective half‐life “teff”)

Calculation: Shorter than either the biological or physical half‐lives.

Depends on:

1. The radiopharmaceutical

2. The organ involved

3. Health state of the organ

4. Personal variations

Production of Radioisotopes / Radionuclides

There are three methods for producing radioisotopes:

1. Cyclotron
2. Nuclear reactor
3. Radionuclide generator

1) Cyclotron:

? Addition proton is forced into a stable nucleus knocking out a neutron ? unstable nucleus with neutron deficit

? Characteristics: – radionuclide formed in the cyclotron can be separated from original stable nuclei (different chemical properties) i.e. can be made carrier free – Short lived (low half life) ? must be used close to the cyclotron ? N.B: other +ve charged ions can be accelerated in the cyclotron (e.g. alpha particles)

Process

nuclear bombardment with high-energy photon

1. Cyclotron consists of a vacuum chamber into which particles are injected into the center

2. They are accelerated in a circular path by high frequency alternating voltage applied between two D-shaped electrodes called “dee’s” which are hollow and allow the particles to move between them

3. Then the particles move in a spiral pattern from the center of the vacuum chamber to the outside by applying a large static magnetic field

4. When the particles’ path leads them to the edge of the cyclotron, they eventually enter the bombardment chamber and interact with the target to produce the radioisotopes.

Cyclotron produced radioisotopes

• Fluorine-18 → used in FDG PET scanning as well as with choline. Created by bombarding Oxygen-18→ rich water with protons to produce 18F→18F has a half-life of 1.87 hours and releases gamma rays with an energy of 511 keV.
• Gallium-67 → used as 67Ga-citrate for imaging of inflammation / tumors
• Thallium-201 → used as 201Tl-chloride in cardiac functional imaging.
• Others → In111 , I123 , Xe133 , C11

2) Nuclear reactor:

? Additional neutron is forced into a stable nucleus? unstable nucleus with neutron excess ? Example: Mo98 + n →Mo99

? Radionuclide formed by the reactors can not be separated from original stable nuclei (same chemical properties) i.e. can not be made carrier free

Process:

1. The core of 235Uranium undergoes spontaneous fission into lighter fragments emitting two or three fission neutrons in the process

2. These fission neutrons then interact with 235U to produce the highly unstable 236U, which carries on the fission event in a self-sustaining nuclear chain reaction

3. Materials can be lowered into ports in the reactor to be irradiated by the neutrons. Neutron capture then creates isotopes of the target element

4. The fission activity can be controlled with control rods that engulf the cores and are made of material that absorbs the neutrons without undergoing fission (e.g. cadmium or boron) preventing further fission events.

5. The moderator rods are made of a material that slows down the energetic fission neutrons. Slower neutrons are more efficient at initiating additional fission events.

Radionuclides produced by neutron activation

• Neutrons are added to isotopes creating a heavy isotope that generally lie above the line of stability. This means they tend to decay in β-emission.
• Only a very small fraction of the target nuclei are activated
• A disadvantage of a nuclear reactor is ? relatively low yield of desired radioisotope and substantial production of other radioisotopes.

Reactor produced radioisotopes (MIX)

• Molybdenum-98 →used in cyclotrons to produce molybenum-99 which decays to technetium-99m
• Iodine-131 →used in treating and in imaging the thyroid gland
• Xenon-133 →used in lung ventilation studies. Half-life of 5 days so can be transported readily unlike krypton-81m (half life of 13 seconds)\

3) Radionuclide generator

1. A slow-decaying parent radionuclide is adsorbed onto a surface such as alumina in a sterile glass column encased in a lead or depleted uranium shield

2. This parent radionuclide decays into the shorter-lived “daughter” radionuclide that will be used for the nuclear imaging

3. The “daughter” radionuclide is removed by passing an eluting solvent (such as sterile saline) through the glass column

4. The resulting solution is collected into a vial, which collects the daughter solvent via a vacuum action

Useful when using a short-lived radionuclide as it needs to be produced near the patient.

Each time the radioisotope is eluted its activity (concentration) drops to zero, then steadily builds up again until reaching maximum to be eluted again.

In case of 99Mo & 99mTc

• Since the Mo and Tc have different chemical properties the Tc can be eluted from the generator by means of a chemical reaction.
• The technetium is washed off (eluted) as sodium pertechnetate
• Transient equilibrium ? At this point the activity of the parent and the daughter is equal, the daughter is decaying as quickly as it is being formed by the decay of its parent (i.e. the daughter and parent decay together with the half-life of the parent, 67 h).
• The eluent (99mTc) decays with its own half-life of 6 h, then regrows with the same half-life.
• After 24 h (4 x 6 hours) → the activity has grown again to a new maximum (equilibrium) value
• Elution can be made daily, though it will be seen that the strength of successive eluents diminishes in line with the decay of 99Mo
• After a week, the generator is replaced and the old one is returned for recycling.

Generator produced radionuclides Technetium-99m, the most commonly used radioisotope, is produced in this way from the longer-lived Molybdenum-99 (created by cyclotrons) which decays via beta decay.

Radiopharmaceuticals

Consist of:

Radionuclide:

Radioactive :

• signal the location of the radiopharmaceutical by emission of gamma rays
• Activity decay by physical half life

Pharmaceutical:

• Determines the physiological behavior of the compound (i.e where the signal accumulates to form the image).
• Its metabolic properties ensure that Radiopharmaceutical is concentrated in the tissue of interest
• Eliminated from these tissues by biological half life

Properties of ideal radioisotope for diagnostic purposes (i.e. not therapeutic):

1. Physical half life : short enough to limit radiation dose to patient but long enough to allow good signal during imaging (ideally 1.5 x length of imaging / similar to the time from preparation to injection)

NB: If the half-life is too short, much more activity must be prepared than is actually injected.

2. Emits gamma rays (no α or β particles) of enough high energy (100 - 300 keV / ideally 150 keV) to leave the body, reach the camera and contribute to the image.

NB:

• Low energy alpha & beta particles are absorbed by the body ? increases the radiation dose to the patient and limits the radiation that reaches the camera to produce the image
• Decay by isomeric transition or electron capture is preferred.

3. Mono-energetic gamma emitter (i.e. gamma rays of one energy), so that scatter can be eliminated by energy discrimination with the pulse height analyzer.

4. Decays to stable daughter isotopes or one with a very long half-life (e.g. 200 000 yrs for 99Tc) with no significant radiation dose to patient

5. Easily and firmly attached to the pharmaceutical at room temperature

6. Doesn’t change behaviour of pharmaceutical (not affect its metabolism)

7. Readily available on the hospital site.

8. Have a high specific activity with low background activity (activity / unit volume).

99mTc used in 90% of radionuclide imaging as it fulfills most of the above criteria:

• Gamma energy 140 keV
• Pure gamma emission
• Good spatial resolution → easily collimated and easily absorbed in thin crystal.
• Relative low noise → reasonably high activity.
• Short half-life (6h) → reasonably large activity can be administered

Properties of the ideal pharmaceutical:

• High target : non-target uptake ratio (localize largely and quickly in the target)
• Readily available and cheap
• Low toxicity
• Stable in vitro and in vitro
• Does not alter physiology in order to give accurate depiction of patient’s physiology
• Eliminated from the body with an effective half-life similar to the duration of the examination → patient dose