nm quiz study 31/10/24

Ideal characteristics of a diagnostic radiopharmaceutical (7)

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

1. TcO4- pertechnetate

2. 99mTcO2 and other 99mTc oxides/hydroxides (hydrolysed 99mTc)

   • oxygen from air/water reacted with reduced 99mTc

3. 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)

1. production is relatively easy (need to be available for use)

2. has a short lived radioisotope and is effective at low doses

   • reduces ionising radiation dose to patients

3. radioactively decays by means needed

   • PET: positron emission

   • SPECT: gamma emitter

4. low chemical toxicity

   • should not harm patient

5. easily administered

   • pico to nanogram size

6. specific uptake and distribution in the body

   • goes to area of interest without a pharmacological effect

How to make radionuclides/radioisotopes (3)

1. nuclear reactor

   • 2 processes, nuclear fission and activation by neutrons

2. particle accelerator (cyclotron)

   • irradiates a stable target with high energy charged particles

3. 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

  1. target captures a neutron (de-excitation and gamma emitted)

     • forms an isotope (most common)

  2. 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

1. fission generates energy as heat

   • need continuous chain of fission reactions

2. heat is added to water to generate steam

3. steam drives a turbine

4. 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

1. radioisotope production

2. radiotracer synthesis

3. quality control

4. 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+

1. electron capture (SPECT)

   • an inner shell electron is captured and a proton turns into a neutron

   • element changes but mass is the same

2. positron emissions (PET)

   • proton changes to a neutron

   • excess positive charge is emitted

Cyclotron principle

• two things that affect the charged particle

1. in an electric field (created by a voltage across 2 electrodes) the particle will be accelerated towards the opposite charged electrode

2. 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

  1. chemically different to parent

     • allow for easy separation

     • usually performed by affinity or ion exchange chromatography

  2. can be eluted with 0.9% saline solution

     • ready for injection

     • must be sterile and pyrogen free

  3. have suitable chemistry to prepare a wide variety of radiopharmaceuticals

     • kit form is best

  4. short half life and gamma emitting radionuclide

     • T1/2 phys = hours-days

  5. parent half life should be short enough so daughter regrowth after elution is rapid

  6. granddaughter product must be either very long lived or stable

     • no additional radiation dose is given to patient by decay of subsequent generations

  7. minimal human intervention needed to elute the daughter

     • minimise radiation dose to operator

  8. 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

1. aluminium (Al3+) ions

2. 99Mo activity

3. 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