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Ideal characteristics of a diagnostic radiopharmaceutical (7)
able to incorporate an ideal imaging radioisotope
localise only in the target organ
for sufficient time to allow physiological processes to be imaged
must behave predictably when administered
must be stable in vivo
must not change patients physiology
simple to prepare
sufficient half life to image pathology
Ideal characteristics of a therapeutic radiopharmaceutical (6)
target only disease and not healthy tissue
high uptake and retention of target organ/system
effective penetration of target tissue
sparing of surrounding tissue
availability of cost
physical half life of radioisotope should match biological half life of carrier compound to maximise absorbed dose in target organ
Tc99m
99mTc is the daughter of 99Mo, a product of 236U fission in a nuclear reactor
99mTc is considered metastable
6 hour half life
99mTc decays to 99Tc with an energy of 140keV
isomeric transition
radiopharmaceutical
chemical compound (pharmaceutical) attached to a radionuclide
pharmaceutical is the carrier molecule to map physiological processes
radionuclide allows external visualisation of where the radiopharmaceutical is localising
radiopharmaceutical must be pharmacologically inert and not interfere with physiological processes
Cold kits
pharmaceutical kits aka cold kits
prepared by manufacturer and have no radiation present
to make a radiopharmaceutical, add radioisotope to kit
aka reconstitution or labelling of kit
99mTc labelling
in Na-99mTcO4, Tc atom is in the +7 oxidation state
it has 7 valence electrons binding to surrounding oxygens
it is stable and unreactive
we need to change the 7+ oxidation number so the 99mTc atom binds to the pharmaceutical in the cold kit instead of the oxygen
we want to remove surrounding oxygens attached to lower the oxidation number
redox reactions → changing oxidation state of an atom
adding and removing electrons
two processes occur together
reduction = atom gains an electron, oxidation number decreases → oxidising agent
oxidation = atom loses an electron, oxidation number increases → reducing agent
we want a reduction to occur in the kit
pertechnetate loses oxygens
most NM cold kits use stannous (tin) ions (Sn2+)
Radiopharmaceutical kits have general features (4)
no air (oxygen) or water anhydrous)
oxygen affects redox reactions
reducing agent for redox reactions
acids and bases to control pH so redox reactions can occur
ie. SnCl2 needs slightly acidic conditions for reduction reaction
99mTc three main impurities
TcO4- pertechnetate
99mTcO2 and other 99mTc oxides/hydroxides (hydrolysed 99mTc)
oxygen from air/water reacted with reduced 99mTc
99mTc/Sn colloids
Sn2+ ions form colloids and reacts with reduced 99mTc-
all reduce amount of RP produced and decrease radiolabelling efficiency of kit
Type 1 RP
2 main components
direct labelling via substitution (strong bonds)
radionuclide = allows for imaging/analysis
can also have a therapeutic benefit ie. 131I
pharmaceutical = allows for selective uptake
specificity to target: tissues, cells, organs
can be proteins, antibodies, sugars, inorganic/organic compounds
uses substitution chemistry
precursor molecule (pharmaceutical) has suitable leaving group
reactions need high temps and anhydrous solvent
pharmaceutical and radionuclide form covalent bonds
type 2 RP
3 main components
radionuclide
pharmaceutical
linker = links radionuclide to pharmaceutical component
needed for metal radionuclides
indirect labelling
for radiometals, uses chelating or prosthetic groups
weak bonds
Design considerations for an effective radiopharmaceutical (6)
production is relatively easy (need to be available for use)
has a short lived radioisotope and is effective at low doses
reduces ionising radiation dose to patients
radioactively decays by means needed
PET: positron emission
SPECT: gamma emitter
low chemical toxicity
should not harm patient
easily administered
pico to nanogram size
specific uptake and distribution in the body
goes to area of interest without a pharmacological effect
How to make radionuclides/radioisotopes (3)
nuclear reactor
2 processes, nuclear fission and activation by neutrons
particle accelerator (cyclotron)
irradiates a stable target with high energy charged particles
generator
Nuclear Reactors
specialised nuclear reactors are used to produce clinically useful radionuclides by
fission or neutron activation of a stable target material
fission
process where a heavy nucleus splits into two smaller nuclei
binding energy for heavy nuclei
~7.2MeV per nucleon
binding energy for intermediate nuclei
~8.2MeV per nucleon
Neutrons Chain reaction
2-3 neutrons are emitted when 235U undergoes fission
available to trigger fission in other nuclei
process of chain reaction
if uncontrolled, violent explosion can occur
critical neutron chain reaction
when chain reaction is self sustained and controlled
sub critical neutron chain reaction
too few neutrons → chain reaction dies out
super critical neutron chain reaction
too many neutrons → run away chain reaction occurs
Neutron activation
2nd nuclear reactor process
can use neutrons produced by 235U fission to bombard a stable target and create radionuclides via neutron capture/neutron activation
two processes can occur
target captures a neutron (de-excitation and gamma emitted)
forms an isotope (most common)
a neutron (fast) is captured and a proton ejected
element has changed
almost all radionuclides produced by neutron activation (neutron added) are unstable → we want this
How does a reactor work and generate electricity
fission generates energy as heat
need continuous chain of fission reactions
heat is added to water to generate steam
steam drives a turbine
electricity is produced
Basic reactor design
control rods
fuel elements
moderator material
coolant
control rods
absorb neutrons, can adjust number of rods to maintain the chain reaction
usually cadmium, boron
fuel elements
consist of enriched uranium (2-4%)
naturally have more 238U
moderator material
slows the fission neutrons by KE transfer so can have another fission event
usually graphite, heavy water
coolant
fission reaction generates heat, which needs to be removed from the reaction chamber and transferred to a steam generator
usually light or heavy water
Nuclear reactor cost and considerations
extremely high investment
$US ~10 billion large and ~1 billion small (2019)
massive shielding and design requirements
high operational $ fuel (~30% operational costs)
staff requirements, security, insurance
waste: long lived radioactive waste is a concern
IAEA regulations
supply logistics, often involves air transport
public safety concerns - Fukushima 2011
Brief history Cyclotron/particle accelerator
1929 invention of Cyclotron
1955 first medical cyclotron at Hammersmith Hospital
1974 first PET camera built for human studies
1975 first PET radiotracer developed
fluorine-18 fluorodeoxyglucose (18F-FDG)
a form of radiolabeled sugar for imaging of glucose metabolism
2000 PET/CT
2009 PET/MRI
Criteria for diagnostic PET radioisotopes (3)
ideally only annihilation photons of 511keV
emitted radiation positron only, no alpha, beta, gamma ray radiation
suitable half life
must match biological half life of system studied
ideally minutes to hours
Positron
positive electron
e+ or beta+
formed by decay of nuclei and is emitted
positron is annihilated by e- and 2 gamma rays emitted (180o)
fundamental basis of PET
PET centre needs
radioisotope production
radiotracer synthesis
quality control
scanning and imaging
PET radioisotope production
nuclear reaction process that uses a particle accelerator/cyclotron
two nuclei are collided together to form a new nucleus
a lighter particle (proton) is accelerated at high energy and collided with a heavier stationary particle (target nucleus)
for protons need >3MeV to initiate nuclear reaction
Cyclotron radionuclides
radionuclide can decay either by EC or beta+
electron capture (SPECT)
an inner shell electron is captured and a proton turns into a neutron
element changes but mass is the same
positron emissions (PET)
proton changes to a neutron
excess positive charge is emitted
Cyclotron principle
two things that affect the charged particle
in an electric field (created by a voltage across 2 electrodes) the particle will be accelerated towards the opposite charged electrode
when in a magnetic field the particle will have a force exerted on it in a direction perpendicular to the magnetic field and to the direction of motion
moves in a circular path
Composition of a cyclotron
ion source
to generate ions
electromagnet
to circulate ions
Dee electrodes
too accelerate ions
Dees = two hollow metal boxes with slight gap in between, where charged particle is introduced (vacuum)
Dees sit in between two poles of a large electromagnet
deflector or stripper foil
to extract ion beam from cyclotron
When potential is added in cyclotron
particle accelerates towards oppositely charged electrode
due to magnetic field, particle moves in a circle
when the ion is circulating in the dee, it enters the gap and voltage is reversed
particle is now attracted to the other dee and accelerates towards it
voltage polarity is switched so acceleration and radius increases
minimum 3MeV
ion speed steadily increases with each successive acceleration
due to the magnetic field the particle follows an increasing spiral path, then it is ready for use
Ion sources and stripper foil
positive ion cyclotrons are less efficient (positive protons)
~30% of beam is lost and not deflected, meaning it does not reach the target: radioactive and magnetic field issues
negative ion cyclotrons (negative hydrogen or deutron)
uses a carbon stripper foil to remove electrons (2 from -H) which yields a positive proton
close to 100% of beam is now available to hit the target
Cyclotron targetry
target material
can be present as a gas, liquid or solid
is held in the cyclotron targetry
must be sealed (vacuum) and cooled (water, helium)
allow quick and easy removal of the radionuclide product
solid target
tends to be smaller than liquids or gases → density of solids is higher
solid can be foil or powder
liquid target
similar dimensions to solid target housing
typically placed within cyclotron, easy to remove and fill
gas targets
uses a cylinder to hold the gas under pressure
beam enters by a small window
targets are quite large in comparison to solid or liquid targets to hold necessary amount of material
Cyclotron common issues
stripper foils burn out → high energy and heat
vacuum issues
power failures
cooling issues
gas line leaks
target - transfer issues
neutron damage
causes
low beam yields
cyclotron won’t start
Radionuclide generators
self contained device housing parent/progeny or parent/daughter relationship in equilibrium
parent isotope (long half life) is produced in a nuclear reactor and sent off in a generator
parent radionuclide decays to a daughter isotope (shorter half life)
daughter isotope is eluted and removed at NM site
Key features of a generator
eluting solvent = usually 0.9% saline which elutes daughter off the column
absorbent = inside the glass column usually alumina or silica (charged)
parent bound tightly
filter = prevents contaminants passing
usually 0.22 micrometres
evacuated vial = where you collect daughter product
lead shielding = for operator safety as parent and daughter emit radiation
Ideal generator systems (8)
daughter product must be
chemically different to parent
allow for easy separation
usually performed by affinity or ion exchange chromatography
can be eluted with 0.9% saline solution
ready for injection
must be sterile and pyrogen free
have suitable chemistry to prepare a wide variety of radiopharmaceuticals
kit form is best
short half life and gamma emitting radionuclide
T1/2 phys = hours-days
parent half life should be short enough so daughter regrowth after elution is rapid
granddaughter product must be either very long lived or stable
no additional radiation dose is given to patient by decay of subsequent generations
minimal human intervention needed to elute the daughter
minimise radiation dose to operator
inexpensive
Parent/daughter decay: equilibrium
the concentration of daughter nuclei in the radioactive equilibrium depends on half lives or decay constants of parent and daughter nuclei
as production rate (daughter) and decay rate (parent) are equal
number of atoms present is always constant over time
a radioactive equilibrium is established after a transition period (a few half lives of the longest lived nucleus)
no equilibrium parent/daughter decay
parent’s T1/2 is less than daughter’s T1/2
daughter activity increases as parent decays
no more daughter is produced when parent is gone
the amount of daughter reduces (decays) with its own half life
secular radioactive equilibrium parent/daughter decay
parent T1/2 is much longer than daughter T1/2
half lives are very different, radioactivity becomes similar after time
features
parent activity is largely unchanged after many daughter half lives
over time daughter activity eventually approaches parent = equilibrium
secular equilibrium is reached ~6 half lives of daughter
parent T1/2 is >100-1000x that of the daughter
transient radioactive equilibrium parent/daughter decay
parent/daughter T1/2 are similar
parent T1/2 is still longer
features
daughter activity increases and exceeds parent
daughter reaches a maximum activity, then decreases and follows parents decay
ratio of parent daughter activities become constant = equilibrium
transient equilibrium is reached in ~4 daughter half lives
parent T1/2 is ~10-100x that of the daughter
for 99mTc, ~24 hours until equilibrium is reached
why are 99mTc RPs most used
convenient supply
decays by emitting 140keV gamma rays (89% abundance)
ideal for gamma cameras
easy chemistry kits
can be administered to patients in low radiation doses
T1/2 6h is sufficient
99Mo/99mTc QC test
aluminium (Al3+) ions
99Mo activity
pH, sterility, pyrogen tests
aluminium (Al3+) ions 99Mo/99mTc QC test
can be washed off alumina column during elution, generally rare
measured colourimetrically
5microg/mL standard
eluate spot must be less intensely coloured than standard spot to pass
99Mo activity 99Mo/99mTc QC test
max allowable 99Mo in eluate is 1kBq of 99Mo per 1Mbq of 99mTc (0.1%)
must not exceed 0.1kBq before 12 hour expiry time
test using dose calibrator and molybdenum shield
pH, sterility, pyrogen tests
desired pH 4-8
Generators cost and practicality
99Mo/99mTc generator
lasts ~2 weeks
~$3-4k
60-300GBq
kit costs vary
68Ge/68Ga generator
lasts months and cost ~$50k
need hot cell ~$75k
reaction module ~$150k
PET camera and staff
planar projection
activity from structures at different depths is overlapped in image
cannot be separated without additional information
observer’s knowledge of anatomy, views from other angles, etc.
tomography
slice images (cross sectional plane) using views from many angles (projections)
no overlap of information from overlying or underlying planes
SPECT
Single Photon Emission Computed Tomography
acquires cross sectional images through three dimensional distribution of a single photon emitting radionuclide within the body of the patient
SPECT vs planar imaging
increase in SPECT image contrast relative to that of an equivalent planar gamma camera image
SPECT is more expensive to perform and more technically complex than planar imaging
SPECT requires a longer acquisition time and often a higher administered activity
SPECT does not replace planar imaging, except where its increased diagnostic potential can be put to good use
raysum
each projection (row of pixels) is formed by a row of holes in a gamma camera collimator
a hole in the collimator sees the gammas along a ray from all depths
pixel signal is called a raysum
Sinogram
particular type of display format having projection angle along the vertical axis and position in each projection along the horizontal axis
a point source of activity in the patient will trace out a sine wave in the sinogram
Radon transform
reconstruction algorithms implement a mathematical operation called the Radon transform
radon transform can construct a set of projection images from a slice image
inverse radon transform can do the reverse with the set of projections
what we measure with the gamma camera in SPECT
the actual radon transforms are mathematically complicated
a mathematical strategy is used
transform the problem into a form where the calculation is simpler
get an answer
apply the inverse transform
Simple backprojection SBP
the counts in each pixel are divided equally along each ray
SBP is too simple
the activity from each single point is distributed along an entire line in the reconstructed image
this blurs the image and implies activity where there is none
Fourier transforms
the Fourier Transform FT of a function gives the required amplitudes at each frequency
the FT of an image is considered transforming from the spatial domain to the frequency domain
benefit of working in frequency domain
working in the frequency domain allows for efficient filtering
enhancement or removal of components of different frequencies
sharp edges and noise (both are represented by large changes from one pixel to the next) are both high frequency effects
Filtered backprojection FBP
modified simple version of simple BP
each projection is FT’d
each FT is filtered using a reconstruction filter
inverse FT’s are applied to produce filtered projections
BP is then performed using modified projections
filtered backprojection reconstruction filter
intended to eliminate 1/r blurring
ideal filter is a ramp filter (exact compensation for 1/r blurring)
increases amplitude of high spatial frequencies and suppresses low frequencies
however, also amplifies high frequency noise → decreases sound to noise ratio SNR
ringing artefacts at edges → use modified filters
Direct Fourier reconstruction
the FT of each projection is calculated
FT’s are overlayed in k-space
k-space values on a regular grid (points) must be interpolated between projections
the inverse FT in 2D of the grid is calculated ( = reconstructed image)
DFR is mathematically rigorous
perfect reconstruction not including noise and imperfect resolution
does not amplify high frequency noise
computationally intensive
interpolation step involves conversion from polar to Cartesian coordinates
therefore not generally used (FBP more practical)
iterative reconstruction
iterative reconstruction acquires/measure projections (SPECT)
construct sinogram of measured data
starting with an initial ‘guess image’, calculate a set of projections that would arise
incorporate attenuation, scatter, septal penetration
=forward projection
construct sinogram of computed projections
compare two sinograms
update ‘guess image’ to yield a better match
repeat 3-6 times until match is sufficiently close
requires a ‘cost function’ to compare two sinograms and determine how well they match
requires an ‘update function’ to adjust the ‘guess image’ based on the results of the sinogram comparison
computationally intensive → each forward recon ~= a FBP
main benefit is improved quantitative accuracy due to inclusion of absorption, scatter, geometry, system resolution
SPECT sampling requirements
it also requires that projections be taken at all (ie. continuous angles)
but
actual projections are digitised/sampled (row of pixels)
we must take projections at a limited set of angles
and
the reconstructed image we want will be digitised
eventually, using more angles won’t provide any more detail if the pixels aren’t fine enough
we can relate the number of projections required (or angular sampling interval) to
spatial resolution of the gamma camera
pixel size of sampled projections
number of pixels in the final image
FOV dimensions
linear undersampling
too few/large pixels used
loss of resolution
artefacts
angular undersampling
too few/large angles used
spoke like artefacts
insufficient angular sampling range
less than 180o used
distortion and artefacts
180o required for complete information
insufficient object coverage
part of object/activity not in all projections
data inconsistent between projections faulty detector element
SNR
sound to noise ratio
CNR
count to noise ratio
SNR and CNR relationship
SNR increases (improves) as the total number of counts making up the entire set of projections increases
for a given pixel size and FOV
for a given number of counts, the SNR decreases if the number of pixels in the FOV is increased
those counts are distributed over a larger number of pixels
the SNR depends on the number of counts per pixel
attenuation in SPECT
attenuation = signal loss due to effects of absorption and scattering
raysum will not be proportional to total activity along ray
measured value will be less than expected value
will underestimate activity in deep tissue
in a large volume of uniform activity, the activity near the centre will appear artificially low = cupping artefact
attenuation varies with photon energy
conjugate counting
attenuation compensation via conjugate counting
also partly corrects for conical acceptance region
projections acquired around a full 360 degrees
pairs of opposite raysums are combined before reconstruction as though it was a 180 projection set
conjugate counting Chang’s method
reconstruct an uncorrected initial image using FBP
using this image, calculate an estimated attenuation path length through the tissue from each pixel for all projection views
mu is kept constant
most SPECT systems use Chang’s methods
best results for brain and abdomen
not as well in thorax and pelvic
significant lung/air and bone
requires projections acquired over 360o
attenuation correction factor calculation
ACF = e^((mu*D)/2)
mu is usually estimated and assumed constant for all tissue types
D is either assumed or estimated