Nuclear Medicine: Nuclear Medicine: Radionuclides, Radionuclides,

Radiopharmaceuticals and Radiopharmaceuticals and Radiation Protection Radiation Protection

Katrina Cockburn, Katrina Cockburn,

Nuclear Medicine PhysicistNuclear Medicine Physicist

What is Nuclear MedicineWhat is Nuclear Medicine

““Diagnostic imaging”Diagnostic imaging” ““Radiotherapy”Radiotherapy” ““Diagnostic testing”Diagnostic testing” ““Make people glow in the dark”Make people glow in the dark” Or… “Nurse”Or… “Nurse”

What makes us different from:What makes us different from:

X-Ray?X-Ray? Linac Radiotherapy?Linac Radiotherapy?

FunctionFunction

What is Nuclear Medicine?What is Nuclear Medicine?

a medical imaging technique in a medical imaging technique in which a pharmaceutical, labelled which a pharmaceutical, labelled with a radioactive substance, is with a radioactive substance, is administered to the patient. The administered to the patient. The amount of radioactivity in various amount of radioactivity in various parts of the body is then parts of the body is then measured with a gamma camerameasured with a gamma camera

Why is this useful?Why is this useful?

Any imaging modality can show what is Any imaging modality can show what is therethere

We use the body’s own physiology to We use the body’s own physiology to indicate and/or treat abnormalities which indicate and/or treat abnormalities which would not be possible using conventional would not be possible using conventional radiology or radiotherapyradiology or radiotherapy

NORMAL BRAIN CTNORMAL BRAIN CT

BRAIN CTBRAIN CT

THIS IMAGE WAS ACQUIRED POST-MORTEM

Why is this useful?Why is this useful?

Why is this useful?Why is this useful?

•CT stage T3 No Mo

•PET/CT stage T3 N2 Mo

Images courtesy of Institute of Nuclear Medicine, University College London

Lymph Node <10mm

Why is this useful?Why is this useful?

•CT staging T4 N2 Mo

•PET/CT staging T4 No Mo

Images courtesy of Institute of Nuclear Medicine, University College London

Why is this useful?Why is this useful?

Additional value of PET-CT in the staging of lung cancer: Additional value of PET-CT in the staging of lung cancer: De Wever et al, 2007.De Wever et al, 2007.

TumourTumour NodeNode MetMet TNMTNM

PET CTPET CT 86%86% 80%80% 98%98% 70%70%

CTCT 68%68% 66%66% 88%88% 46%46%

PETPET 46%46% 70%70% 96%96% 30%30%

Co-ReadCo-Read 72%72% 68%68% 96%96% 54%54%

Over-staging: PET-CT T=8%, N=16%, CT T=16%, N=20%Over-staging: PET-CT T=8%, N=16%, CT T=16%, N=20%

Under-Staging: PET-CT T=6%, N=4%, CT T=12%, N=6%Under-Staging: PET-CT T=6%, N=4%, CT T=12%, N=6%

Components of NM ProceduresComponents of NM Procedures

Radiopharmaceutical

Detection Device

Analysis

RadiopharmaceuticalRadiopharmaceutical

Two functions: Two functions: Pharmaceutical – acts as tracerPharmaceutical – acts as tracer Radioactive material – allows us to monitor Radioactive material – allows us to monitor

distributiondistribution

Both functions may be performed by the Both functions may be performed by the radioactive isotope radioactive isotope I-123 thyroid imaging I-123 thyroid imaging

Or isotope may need to be chemically bound to Or isotope may need to be chemically bound to a pharmaceuticala pharmaceutical Tc99m – HDP for bone scansTc99m – HDP for bone scans

Properties of Radioactive MaterialsProperties of Radioactive Materials

May emit x-rays, gamma-rays, electrons or May emit x-rays, gamma-rays, electrons or alpha particlesalpha particles There may be one or more of these emitted There may be one or more of these emitted Daughter products may also be radioactiveDaughter products may also be radioactive Gamma rays will have “characteristic” Gamma rays will have “characteristic”

energiesenergies

Decay exponentially Decay exponentially

The Ideal RadiopharmaceuticalThe Ideal Radiopharmaceutical PharmaceuticalPharmaceutical

Short biological half-lifeShort biological half-life Localise only in the area Localise only in the area

of interestof interest Should not alter Should not alter

physiological system physiological system under examinationunder examination

Minimal/No side effectsMinimal/No side effects

RadionuclideRadionuclide Short physical half-lifeShort physical half-life Pure Gamma EmitterPure Gamma Emitter Energy 100-200keVEnergy 100-200keV Suitable for Suitable for

incorporation into a incorporation into a pharmaceuticalpharmaceutical

Readily availableReadily available

Easy to prepareEasy to prepare Labelling Labelling StabilityStability

Mechanisms of Localisation In-VivoMechanisms of Localisation In-Vivo

Active Cellular TransportActive Cellular Transport potassium analogues in myocardial imagingpotassium analogues in myocardial imaging

Simple diffusionSimple diffusion Kr-81m in lung ventilation Kr-81m in lung ventilation

Capillary BlockadeCapillary Blockade Tc99m-MAA for lung perfusionTc99m-MAA for lung perfusion

Physiochemical adsorptionPhysiochemical adsorption Phosphates localising in mineral phase of bonePhosphates localising in mineral phase of bone

AntibodiesAntibodies Labelled antibodies for tumour imagingLabelled antibodies for tumour imaging

Commonly Used RadionuclidesCommonly Used Radionuclides

RadionuclideRadionuclide ProductionProduction Photon Energy Photon Energy (keV)(keV)

Half-LifeHalf-Life

Tc99mTc99m GeneratorGenerator 140140 6h6h

Tl201Tl201 CyclotronCyclotron 68-80 (x-rays)68-80 (x-rays) 74h74h

I123I123 CyclotronCyclotron 160160 13h13h

In111In111 CyclotronCyclotron 173, 247173, 247 67h67h

F18F18 CyclotronCyclotron 511*511* 110 min110 min

Rb82Rb82 GeneratorGenerator 511*511* 75 sec75 sec

I131I131 ReactorReactor 280, 360, 640280, 360, 640 8 days8 days

* Annihilation photons produced in pairs

Radionuclide GeneratorsRadionuclide Generators

Solution to the problem of supply of short-Solution to the problem of supply of short-lived radionuclides (e.g. Tc99m, Rb82)lived radionuclides (e.g. Tc99m, Rb82)

Principle:Principle:

Daughter radionuclide Daughter radionuclide with shorter half-lifewith shorter half-life

Relatively long Relatively long lived parent lived parent radionuclideradionuclide

DecayDecay

ElutionElution

Remove ‘daughter’ radionuclide Remove ‘daughter’ radionuclide No removal of ‘parent’ radionuclideNo removal of ‘parent’ radionuclide SterileSterile

TechniquesTechniques PrecipitationPrecipitation DistillationDistillation Ion exchangeIon exchange + Others+ Others

Mo99 Decay SchemeMo99 Decay Scheme

Mo99 (TMo99 (T½ ½ = = 67h)67h)

Tc99m (TTc99m (T½ ½ = 6h)= 6h)

Tc99 (TTc99 (T½ ½ = 2.1x10= 2.1x1055 years)years)

Ru99 (stableRu99 (stable))

ββ-- (91.4%) (91.4%)

ββ-- (8.6%) (8.6%)γγ

ββ--

Ion ExchangeIon Exchange

Eluent Eluent ReservoirReservoir

One-way air One-way air filterfilter

Mo99 Mo99 Absorbed Absorbed onto onto AluminaAlumina EvacuateEvacuate

d Viald Vial

FilterFilter

Lead/ Depleted Lead/ Depleted Uranium Uranium ShieldShield

NaNa++ClCl-- NaNa++(TcO(TcO44))--GeneratGeneratoror

Tc99m GeneratorTc99m Generator

0

20

40

60

80

100

120

0 24 48 72 96 120 144 168 192

Time (Hours)

Ac

tiv

ity

Mo99Mo99

Tc99Tc99mm

Transient Transient EquilibriuEquilibriumm

Tc99m Generator with ElutionTc99m Generator with Elution

0

20

40

60

80

100

120

0 24 48 72 96 120 144 168 192

Time (Hours)

Act

ivit

yMo99Mo99

Tc99Tc99mm

Radio-Labelling with Tc99mRadio-Labelling with Tc99m

Cold KitsCold Kits Pre-packed set of sterile ingredients designed Pre-packed set of sterile ingredients designed

for the preparation of a specific for the preparation of a specific radiopharmaceuticalradiopharmaceutical

Typical IngredientsTypical Ingredients Compound to be complexed to the Tc99m Compound to be complexed to the Tc99m

e.g. methylene diphosphonate (MDP)e.g. methylene diphosphonate (MDP)

Stannous Ions (SnStannous Ions (Sn++)) Stablilsers, buffers, antioxidants, bactericidesStablilsers, buffers, antioxidants, bactericides

Cyclotron and PET isotopesCyclotron and PET isotopes

Most PET isotopes are produced in Most PET isotopes are produced in cyclotronscyclotrons F18, C11, O15F18, C11, O15

Positron emitters have “too many” protons Positron emitters have “too many” protons for stabilityfor stability

Normally produced by smashing protons Normally produced by smashing protons into stable targetsinto stable targets

To make F18, fire protons into O18 To make F18, fire protons into O18 enriched waterenriched water

Nuclear Reaction for F-18Nuclear Reaction for F-18

Proton fired at oxygen-18Proton fired at oxygen-18 O-18 absorbs the proton O-18 absorbs the proton

Temporary creation of fluorine-19Temporary creation of fluorine-19 Emission of neutronEmission of neutron

Creation of fluorine-18Creation of fluorine-18

Oxygen -18

8 protons, 10 neutrons

protonFluorine – 18

9 protons, 9 neutronsneutron

Physics of the cyclotronPhysics of the cyclotron

Charged particles move in circles in a Charged particles move in circles in a static magnetic fieldstatic magnetic field

The size of the circle depends on the The size of the circle depends on the energy of the particleenergy of the particle

Electric fields can be used to accelerate Electric fields can be used to accelerate particlesparticles

Cyclotron uses both types of fields to Cyclotron uses both types of fields to accelerate a beam of protons into a targetaccelerate a beam of protons into a target

Diagram of a cyclotronDiagram of a cyclotron

ABT Desk-top cyclotronABT Desk-top cyclotron

Radiopharmacy QARadiopharmacy QA

Radionuclide PurityRadionuclide Purity Mo99 ‘Breakthrough’Mo99 ‘Breakthrough’ Aluminium Aluminium Other Radioactive contaminants Other Radioactive contaminants

(fission impurities)(fission impurities)

Radiochemical PurityRadiochemical Purity Free Tc99mFree Tc99m

Different bio-distributionDifferent bio-distribution Unnecessary radiation of organsUnnecessary radiation of organs MisdiagnosisMisdiagnosis

SterilitySterility Aseptic techniquesAseptic techniques Routine monitoring for microbiological, particulate, and Routine monitoring for microbiological, particulate, and

radioactive contaminationradioactive contamination

first eluate from each generatorfirst eluate from each generator}}Quality guaranteed by Quality guaranteed by

manufacturermanufacturer

}} First vial of new batch for First vial of new batch for

commercial kitscommercial kits

All kits for unlicensed All kits for unlicensed productsproducts

Radionuclide CalibratorRadionuclide Calibrator

Ionisation ChamberIonisation Chamber Acceptance TestingAcceptance Testing

Check against national or Check against national or secondary standardssecondary standards

Daily QADaily QA Long Lived SourceLong Lived Source Source assayed using several radionuclide Source assayed using several radionuclide

settingssettings

Geometrical DependenceGeometrical Dependence

Factors Affecting the DoseFactors Affecting the Dose Administered ActivityAdministered Activity

Diagnostic Reference Levels (ARSAC)Diagnostic Reference Levels (ARSAC)

Effective Half-LifeEffective Half-Life

Bio-DistributionBio-Distribution Radiochemical purityRadiochemical purity PathologyPathology DrugsDrugs

Type of radioactive decayType of radioactive decay

Energy of emissionsEnergy of emissions

biolphyseffective 111

Patient DosimetryPatient Dosimetry

The Cumulated The Cumulated Activity: Activity: ÃÃss

The activity of the The activity of the radiopharmaceutical radiopharmaceutical within a given organ within a given organ integrated over timeintegrated over time

Depends on the Depends on the effective half lifeeffective half life

Patient DosimetryPatient Dosimetry

The “S-Factor”, SThe “S-Factor”, S Published by MIRDPublished by MIRD S(t,s) = D f(t,s) / m S(t,s) = D f(t,s) / m

D = Total energy from the radiation typeD = Total energy from the radiation type f(t,s) = the fraction of the energy absorbed by f(t,s) = the fraction of the energy absorbed by

the target organ (t) which is emitted by the the target organ (t) which is emitted by the source organ (s)source organ (s)

m = the mass of the target organm = the mass of the target organ

Patient DosimetryPatient Dosimetry

Dose to the target organ, DDose to the target organ, Dtt

Takes into account dose from activity Takes into account dose from activity within the target organ within the target organ andand all other all other organsorgans

Patient DosimetryPatient Dosimetry

Need to account Need to account for differing for differing radiosensitivities: radiosensitivities:

Use ICRP Use ICRP weighting factors weighting factors for different for different organs to get the organs to get the Effective Dose, HEffective Dose, H

Radiopharmaceuticals and dosesRadiopharmaceuticals and dosesRadio-Radio-

pharmaceuticalpharmaceuticalRouteRoute Typical Activity Typical Activity

(MBq)(MBq)Effective Effective

Dose (mSV)Dose (mSV)Clinical UseClinical Use

Tc99m-MDPTc99m-MDP i.v.i.v. 600600 33 Bone ImagingBone Imaging

Tc-99m-DTPATc-99m-DTPA InhaledInhaled 2020 0.10.1 Lung Lung VentilationVentilation

Tc-99m-MAATc-99m-MAA i.v.i.v. 100100 11 Lung Lung PerfusionPerfusion

Tl-201 (thallous Tl-201 (thallous chloride)chloride)

i.v.i.v. 8080 1818 Myocardial Myocardial PerfusionPerfusion

I-131-sodium I-131-sodium iodideiodide

oraloral 400400 2424 Thyroid Thyroid metastasesmetastases

Tc99m- labelled Tc99m- labelled red cellsred cells

i.v.i.v. 800800 88 Cardiac blood Cardiac blood poolpool

Tc99m-labelled Tc99m-labelled white cellswhite cells

i.v.i.v. 200200 33 Localisation of Localisation of infectioninfection

Protection of the PatientProtection of the PatientIR(ME)RIR(ME)R

Referral CriteriaReferral Criteria Justification (ARSAC license holder)Justification (ARSAC license holder) Patient identification proceduresPatient identification procedures Labelling of syringes/vialsLabelling of syringes/vials Checking of activity prior to administrationChecking of activity prior to administration Protective clothingProtective clothing Thyroid BlockingThyroid Blocking Conception, Pregnancy, Breast FeedingConception, Pregnancy, Breast Feeding

Protection of the PatientProtection of the PatientMARS and ARSACMARS and ARSAC

Certification of medical and dental Certification of medical and dental practitioners practitioners

Certificates last for 5 yearsCertificates last for 5 years Specific to individual practitionerSpecific to individual practitioner Specific to individual siteSpecific to individual site Named radiopharmaceuticals and usesNamed radiopharmaceuticals and uses Notes for GuidanceNotes for Guidance

PregnancyPregnancy

Policy to check for pregnancy in female patients Policy to check for pregnancy in female patients of child bearing age of child bearing age

Notices in departments “Please inform Notices in departments “Please inform technicians if you may be pregnant”technicians if you may be pregnant”

Does the risk to the foetus outweigh the risk to Does the risk to the foetus outweigh the risk to the patient from failure to diagnose and treatthe patient from failure to diagnose and treat Clinical benefit to the mother may be of indirect Clinical benefit to the mother may be of indirect

benefit to the unborn child benefit to the unborn child

Conception: Advice to MalesConception: Advice to Males

No evidence that pre-conceptual irradiation of No evidence that pre-conceptual irradiation of males can cause any abnormality in their males can cause any abnormality in their offspringoffspring**

No need to avoid conception for males undergoing No need to avoid conception for males undergoing routine diagnostic studiesroutine diagnostic studies

Therapeutic administration of long-lived Therapeutic administration of long-lived radionuclides (e.g I-131, Sr-89)radionuclides (e.g I-131, Sr-89) Possible appearance of larger quantities of such Possible appearance of larger quantities of such

radionuclides in spermradionuclides in sperm Avoid conception for 4 monthsAvoid conception for 4 months

**Doll R et al. Nature 1994;367:678-Doll R et al. Nature 1994;367:678-680680

Conception: Advice to FemalesConception: Advice to Females

No need to avoid pregnancy after diagnostic procedures No need to avoid pregnancy after diagnostic procedures using radiopharmaceuticals with a physical half-life using radiopharmaceuticals with a physical half-life <7days<7days**

Diagnostic use of Longer Lived Radiopharmaceuticals:Diagnostic use of Longer Lived Radiopharmaceuticals: Se75 (adrenal imaging): 12 monthsSe75 (adrenal imaging): 12 months I131-MIBG (tumour imaging): 2 monthsI131-MIBG (tumour imaging): 2 months I131 (thyroid metastases): 4 monthsI131 (thyroid metastases): 4 months

TherapyTherapy I131 (≤800 MBq for treatment of thyrotoxicosis): 4 monthsI131 (≤800 MBq for treatment of thyrotoxicosis): 4 months P32 (≤200 MBq for treatment of polycythemia): 3 monthsP32 (≤200 MBq for treatment of polycythemia): 3 months Sr89 (≤150 MBq for treatment of bone metastases): 24 monthsSr89 (≤150 MBq for treatment of bone metastases): 24 months

**ARSAC Notes for Guidance Dec 1998 ARSAC Notes for Guidance Dec 1998 p25p25

Breast FeedingBreast Feeding

Can the test be delayed?Can the test be delayed? Mother to express breast milk prior to testMother to express breast milk prior to test Advise to stop breast feeding for time Advise to stop breast feeding for time

depending upon radiopharmaceuticaldepending upon radiopharmaceutical Any I131-iodide: STOPAny I131-iodide: STOP 80 MBq Tc99m-MAA: 12 hours80 MBq Tc99m-MAA: 12 hours 800 MBq Tc99m-DTPA: 0 hours800 MBq Tc99m-DTPA: 0 hours

Radiation ProtectionRadiation ProtectionIRRIRR

Time, Distance, ShieldingTime, Distance, Shielding Handling techniques to reduce timeHandling techniques to reduce time ForcepsForceps Syringe ShieldsSyringe Shields

ContaminationContamination Surfaces in rooms to be smooth and non-absorbentSurfaces in rooms to be smooth and non-absorbent IsolatorsIsolators Protective ClothingProtective Clothing No eating or drinking in rooms where unsealed sources No eating or drinking in rooms where unsealed sources

handledhandled Wash hand basins close to the exit of roomsWash hand basins close to the exit of rooms

Routine contamination monitoringRoutine contamination monitoring Room surfaces and staff leaving controlled areasRoom surfaces and staff leaving controlled areas

Radiation protection Radiation protection fromfrom patients patientsIRR IRR

In general no restrictions or precautions In general no restrictions or precautions for diagnostics proceduresfor diagnostics procedures Exceptions:Exceptions:

>10MBq In111-WBC, >120MBq In111 Octreotide>10MBq In111-WBC, >120MBq In111 Octreotide >200MBq Ga67 citrate, >30MBq I-131>200MBq Ga67 citrate, >30MBq I-131 If the work of the patient is radiosensitiveIf the work of the patient is radiosensitive Assessment of exposure and contamination riskAssessment of exposure and contamination risk

TherapyTherapy

Procedures on WardsProcedures on Wards

ContaminationContamination Ward staff will be protected if they follow Ward staff will be protected if they follow

standard hygiene procedures (e.g. standard hygiene procedures (e.g. gloves/aprons)gloves/aprons)

Handling & storage instruction should Handling & storage instruction should bedding/clothing become contaminatedbedding/clothing become contaminated

Direct IrradiationDirect Irradiation No special precautions usually requiredNo special precautions usually required Risk assessment if patient require intensive Risk assessment if patient require intensive

nursingnursing

Keeping & Disposal of Radioactive Keeping & Disposal of Radioactive SubstancesSubstances

EPR Certificates for storage and disposal EPR Certificates for storage and disposal of radioactive materialsof radioactive materials

Properly designed storesProperly designed stores Stock RecordsStock Records Reports to be sent to the Environment Reports to be sent to the Environment

AgencyAgency Solid waste for incinerationSolid waste for incineration Solid waste to landfillSolid waste to landfill Aqueous waste to drainsAqueous waste to drains

Transport of Radioactive MaterialsTransport of Radioactive Materials

Controlled under Carriage of Dangerous Controlled under Carriage of Dangerous Goods 2009Goods 2009

Drivers need to be Drivers need to be trainedtrained

Vehicles need to beVehicles need to be marked marked

Emergency kits andEmergency kits andinstructionsinstructions