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Radiofarmaca
basisbegrippen
VZA 1/10/2019
Guy Bormans
Radiofarmaceutische Research KU Leuven www.radiopharmacy.be
Wetgeving
KB 4/3/1991 normen ziekenhuisapotheek
Art.9 opdrachten ziekenhuisapotheker :
9° Het toezicht houden op de galenische bereiding van inspuitbare radiofarmaceutische
preparaten.
KB 20/7/2001 algemeen reglement op de bescherming van de bevolking, van de
werknemers en het leefmilieu tegen het gevaar van de ioniserende stralingen (ARBIS)
Art 54.8.2. Verplichtingen inzake bescherming en toezicht
De persoon die vergund is om radionucliden in bezit te houden en te gebruiken:
f. treft de nodige maatregelen om de toegang tot de lokalen en een doeltreffende
bescherming in de zin van artikel 2 te verzekeren voor de persoon belast met de
uitoefening van het toezicht op de galenische bereiding van inspuitbare radio-farmaceutische
bereidingen, overeenkomstig het koninklijk besluit van 4 maart 1991
houdende vaststelling van de normen waaraan een ziekenhuisapotheek moet voldoen om te
worden erkend.
201?
Nieuw KB ziekenhuisapotheken gebaseerd op PICs guide: ?
radioisotopes
#protons
#neutrons
p=n
P+N>>>
fission/a emission
Proton excess
p+n+e
+ + v (
+-decay)
918
818F O
p++e
-n+ v (electron capture)
81201
80201Tl Hg
Neutron excess np
++e
-+v
53131
54131I Xe
Isomeric transition
From excited state to ground state= 99mTc 99Tc + γ (140 keV)
Type of radiation
Particulate radiation:
a-radiation: 2p + 2n (He-nucleus)
--radiation: electrons
+-radiation: positrons
neutrons
electromagnetic radiation:
X-rays, -rays
High LET
(linear energy transfer)
Strong cel damage
Can not be detected externally
THERAPY
Low LET
Relatively low cel damage
Can be detected externally
only pmol radionuclide required
Tissue is transparent for X/γ
IMAGING
The body is transparant for gamma radiation
Radionuclides can be “tracked” in the body by
external detection of gamma radiation
SPECT single photon emission
tomography
PET positron emission tomography
Image contrast depends on local
concentration of the radionuclide
amounts of radionuclides for medical use
A=N*λ
Typical nanogram (10-9 g) range
No pharmacologic side effects (“tracer principle”)
Sometimes side effects from additives and precursors
Radiopharmacological side effects are possible (longlived beta or gamma-emitters)
Polonium-210 colloid (a-straler)
Concentrates in liver and spleen
Lethale dose (oral) : 50 ng
Not detectable externally
Alexander Litvinenko
Radiopharmaceuticals
Vector molecule:
Specific molecular interaction
(receptor, transporter, enzyme,…):
Responsible for imaging contrast
for molecular imaging (diagnosis)
Radionuclide:
Emits upon decay externally
detectable gamma or X rays
Vectormolecule:Radionuclide:
Emits upon decay particulate
radiation fordestruction of
target cells
Radiopharmaceuticalsfor therapy
Specific molecular interaction
(receptor, transporter, enzyme,…)
Responisble for irradiation selectivity
vector
Vectorisation of radiopharmaceuticals
•Installation in specific compartment
•Gas inhalation (lung ventilation)
•Radioactive food and drink (stomach evacuation)
•Substrate for transporter system
•Physical transport (eg glomerular filtration kidney)
•Molecular transport (eg NaI (NIS symporter; organic anion
transporter (liver); tubular secretion (kidney);
neurotransmitter transporters (e.g. dopamine transporter)
vector
•(pseudo)-irreversible trapping
• Physical trapping in capillaries (99mTc-macroaggregates)
• Colloidal particles by the RES
• Metabolic fixation/substrate for enzyme and trapping of
reaction product
• Alkylation of biomolecule (covalent binding)
•Equilibrium binding
•Immunological interaction (labelled antibodies)
•receptor interaction
Choice of radionuclideDiagnosis Therapy
decay IT, electron capture,
β+
β-, a, EC
Halflife 1-24h-4d 3-20 d
Gamma-energy 100-200 keV (511
keV PET)
Cost
availability Cyclotron,
generator (99mTc; 68Ga)
Nuclear reactor,
generator
Chemistry Efficiënt and fast conjugation to vector
molecules, without changing the
biologic characteristics of the vector
Radionuclides for imaging
12
Radio-
nuclide
Half-
life
Mode
of
decay
β+
Emax
(keV)
range
in H2O
(mm)
Chemistry production CNS
tracers
antibodies peptides
13N 9.97 min β+ (100%) 1198 keV
5.1 mm
Very fast
organic
chemistry
Cyclotron
Liquid target16O (p,α)
11C 20.4 min β+ (100%) 960 keV
3.9 mm
Fast organic
chemistry
Cyclotron
Gas target14N(p,α)
68Ga 68 min β+ (89%)
EC (11%)
1899 keV
8.9 mm
Chelation
chemistry
Generator68Ge-68Ga
18F 109.8
min
β+ (97%)
EC (3%)
634 keV
2.3 mm
Fast organic
chemistry
Cyclotron
Liquid target18O(p,n)
89Zr 78.4 h β+ (100%) 897 keV
3.6 mm
Chelation
chemistry
Cyclotron
Solid trarget89Y(p,n)
124I 4.17 d β+ (23%)
EC (77%)
1535
keV(50%)
6.9 mm
2138 keV
(50%)
10.2 mm
Organic
chemistry
Cyclotron
Solid target124Te(p,n)
99mTc 6h Isomeric
transition
n/a Chelation
chemistry
(reduction of Tc
required)
generator
Radiopharmaceutical Research13
Production of radiopharmaceutical
Production of radionuclide
cyclotron
generator
Nuclear reactor
Incorporation of radionuclide in target molecule
(conjugation to the vector)Chelation (complexation)
Fast, efficient, aqueous solution
Not for small molecules
Organic chemistry
Organic solvents, purification
Not for biologicals
QC
Radionuclides for imaging
14
Radio-
nuclide
Half-
life
Mode
of
decay
β+
Emax
(keV)
range
in H2O
(mm)
Chemistry production CNS
tracers
antibodies peptides
13N 9.97 min β+ (100%) 1198 keV
5.1 mm
Very fast
organic
chemistry
Cyclotron
Liquid target16O (p,α)
11C 20.4 min β+ (100%) 960 keV
3.9 mm
Fast organic
chemistry
Cyclotron
Gas target14N(p,α)
68Ga 68 min β+ (89%)
EC (11%)
1899 keV
8.9 mm
Chelation
chemistry
Generator68Ge-68Ga
18F 109.8
min
β+ (97%)
EC (3%)
634 keV
2.3 mm
Fast organic
chemistry
Cyclotron
Liquid target18O(p,n)
89Zr 78.4 h β+ (100%) 897 keV
3.6 mm
Chelation
chemistry
Cyclotron
Solid trarget89Y(p,n)
124I 4.17 d β+ (23%)
EC (77%)
1535
keV(50%)
6.9 mm
2138 keV
(50%)
10.2 mm
Organic
chemistry
Cyclotron
Solid target124Te(p,n)
99mTc 6h Isomeric
transition
n/a Chelation
chemistry
(reduction of Tc
required)
generator
Radionuclides for radionuclide therapy: β- emitters
15
Radionuclides for radionuclide therapy: α emitters
16
Radionuclide generator
• Dochternuclide van langerlevend moedernuclide is zelf radioactief
• Bij verval moedernuclide wordt dochternuclide aangemaakt
• Scheiding van dochternuclide en moedernuclide (blijft in de generator)
Radionuclide generator:
langerlevend moedernuclide vervalt naar dochternuclide
99Mo 99mTc
-
42 43
IT99Tc43
t
ln(activiteit)
t
ln(activiteit)
Scheiding van dochter en moedernuclide
Elutie van de generatorkolom:
Dochternuclide wordt van de generator geëlueerd
Moedernuclide blijft op de kolom
99Mo 99mTc
-
42 43
IT99Tc43
Ingroei van dochternuclide door verval moedernuclide
t
99Mo 99mTc
-
42 43
IT99Tc43
Radiopharmaceutical Research21
Radiopharmaceuticals: classificationPreparation• Ready for use
• (Kit) preparation99mTc-radiopharmaceuticals68Ga-radiopharmaceuticals
Addition of (registered) generator eluate to
(registered) labelling kit
(similar to reconstitituion of antibiotic)
LAF hood
Simple QC
• manufacteringPET-radiopharmaceuticals (18F/11C)
Extensive “organic chemistry” synthesis procedure
synthesis module including preparative HPLC
hotcells- clean room
Extensive QC/need for radiopharmacist
+
Radiopharmaceutical Research22
QC of radiopharmaceuticals
-chemical purity: (non-radioactive) chemical impuritues
-radiochemical purity: desired radionuclide in undesired chemical form
-radionuclidical purity: undesired radionuclide
-microbiological purity: bacteria, molds, endotoxins,…
Radiopharmaceutical Research23
QC of radiopharmaceuticals
-chemical purity
99mTc-radiopharmaceuticals: kit labeling
Chemical purity labeling kit is responsibility of the
manufacterer of cold kits and generator
3.15 mg oxidronate sodium
0.26 mg, SnCl2 (reducing agent)
0.84 mg gentisic acid (stabilizer)
30.0 mg sodium chloride
+ 99mTcO4-
10 µg 99mTc-oxidronate
3.15 mg oxidronate sodium
0.26 mg, SnCl2 (reducing agent)
0.84 mg gentisic acid (stabilizer)
30.0 mg sodium chloride
Chemical composition labeling kit
(almost) doesn’t change
99Mo-99mTc
generator
Radiopharmaceutical Research24
QC of radiopharmaceuticals
-radiochemical purity
99mTc-radiopharmaceuticals: kit labeling
Technetium-99m in an undesired chemical form
(99mTcO4- , 99mTcO2)
3.15 mg oxidronate sodium
0.26 mg, SnCl2 (reducing agent)
0.84 mg gentisic acid (stabilizer)
30.0 mg sodium chloride
+ 99mTcO4-
10 µg 99mTc-oxidronate
3.15 mg oxidronate sodium
0.26 mg, SnCl2 (reducing agent)
0.84 mg gentisic acid (stabilizer)
30.0 mg sodium chloride
99mTcO2
Count
activity
99mTcO2
99mTc-oxidronate
+ 99mTcO4-
(quantitative)
1000 fold higher amount of
chelator compared to 99mTc
labelled radiopharmaceutical
Radiopharmaceutical Research25
QC of radiopharmaceuticals
-radionuclidical purity
99mTc-radiopharmaceuticals: kit labeling99Mo breakthrough from the generator99Mo halflife = 66h, β- emitter
(high radiation dose)
+ 99mTcO4-
10 µg 99mTc-oxidronate
? 99MoO42-
+ 99MoO42-Gamma spectrometry
Dose calibrator
Radiopharmaceutical Research26
QC of radiopharmaceuticals
-microbiological purity
99mTc-radiopharmaceuticals: kit labeling
Sterile generator
GMP producedSterile kit
GMP produced
Aseptic reconstitution
Aseptic dose fractionation
(multidose vial)
Sterility test (can also be used for media fills)
endotoxin test
27
QC of radiopharmaceuticals
-chemical purityPET-radiopharmaceuticals: organic synthesis
Chemical purity is responsibility of the PET production centre
CH3CN
NaOH
Organic solvent: gas chromatography
Strong base: pHNasty reagent: TLC, HPLC18O(p,n)18F
18FDG
2-[18F]fluoro-2-deoxy-D-glucose
28
QC of radiopharmaceuticals
-chemical purity
Radioactivity detection
mass detection
18FDG
[18F]fluoro-2-deoxy-D-glucose
Molar activity: amount of nmol/Bq
FDG
[18+19F]fluoro-2-deoxy-D-glucose
Usually ng
Usually µg
1000-fold
“contamination”!
PET-radiopharmaceuticals: organic synthesis
PET radiopharmaceutical can be “contaminated” by stable
isotope homologue
29
QC of radiopharmaceuticals
-radiochemical purityPET-radiopharmaceuticals: organic synthesis
radiochemical purity is responsibility of the PET production
centre
CH3CN
NaOH
18F-fluoride that did not react:TLC/HPLC18O(p,n)18FIncomplete hydrolysis Ac-18FDG (TLC/HPLC)
Racemisation:18FD mannose (HPLC)
radioHPLC: identification, chemical and radiochemical purity
30
QC of radiopharmaceuticals
-radionuclidical purity
PET-radiopharmaceuticals: organic synthesis
radionuclidical purity is responsibility of the PET production
centre, but usually not a problem since PET tracers are HPLC
purified18O(p,n)18F
Nuclear side reactions
Long lived radionuclides from activation
of target foils
Gamma spectrometry
31
QC of radiopharmaceuticals
-microbiological purity
PET-radiopharmaceuticals: organic synthesis
Microbioogical purity is responsibility of the PET production
centre
Low bioburden: sterile disposible
cassettes for radiosynthesis
Class C room
Class C
Hotcell
Radiosynthesis
Class B passbox Class A passbox
Class A dispensing cell
Sterile filtration and dispensing
32
QC of radiopharmaceuticalsPET-radiopharmaceuticals: organic synthesis
Microbioogical purity is responsibility of the PET production
centre
Class C room
Class C
Hotcell
Radiosynthesis
Class B passbox Class A passbox
Class A dispensing cell
Sterile filtration and dispensing
Radiopharmaceutical Research33
Release flow PET (t)racer
ProductionCyclotron
production
Radiosynthesis
HPLC purification
Filtration and
formulation
Pre-release QC
HPLC
TLC
GC
pH
Half-life
Conditional
release
Post-release QC
Sterility
endotoxins
Longlived
radionuclides
Patient
injection
0.5-1h +20 min
Final
release
+14 days
• They make only nanograms of “active” ingredient costing >100 M€/mg
• They can only use their pharmaceuticals for a couple of hours
• Their active ingredients are usually contaminated with a thousand-fold stable
isotope homologue or chelator
Radiopharmaceutical Research34
The worlds worst pharmacists are radiopharmacists
Worlds worst
pharmacist
Radiopharmaceutical Research35
Protection of radiopharmaceutical against environment
Biohazard vertical flow
LAF hood
Class C/D environment
99mTc-radiopharmaceuticals
Radiopharmaceutical Research36
Protection of radiopharmaceutical against environment
Class C room
Class C
Hotcell
Radiosynthesis
underpressure
Class B passbox
overpressure
Class A passbox
overpressure
Class A dispensing cell
Sterile filtration and dispensing
overpressure
18F/11C-radiopharmaceuticals
Protection of radiopharmaceutical against environment
Pressure hill:
Avoids microbiologically
contaminated air from getting in
Avoids radioactively
contaminated air from getting out
Radiopharmaceutical Research38
Protection of environment against radiopharmaceutical
2 risks:
1. (airborne) contamination: underpressure
2. Irradiation: shielding (Pb)
Radiopharmaceutical Research39
Protection of environment against radiopharmaceutical
Biohazard vertical flow
LAF hood:
underpressure Lead/Leadglass shielding
10 mm Pb
99mTc-radiopharmaceuticals
Radiopharmaceutical Research40
Class C room
Class C
Hotcell
Radiosynthesis
underpressure
Class B passbox
overpressure
Class A passbox
overpressure
Class A dispensing cell
Sterile filtration and dispensing
overpressure
18F/11C-radiopharmaceuticals
Protection of environment against radiopharmaceutical
Shielding
7.5-10 cm Pb
Pressure hill:
Avoids microbiologically
contaminated air from getting in
Avoids radioactively
contaminated air from getting out
Protection of environment against radiopharmaceutical
Protection of environment against radiopharmaceutical:
shielding
Protection of environment against radiopharmaceutical
Radionuclide therapy isolation room
Protection of environment
against radiation and contamination
Specific risks of radiopharmaceuticalsApplication
• Diagnosis
• Therapy
Highest risk is associated with I.V. injection, microbiological contamination
Altered distribution (radiochemical purity, misadministration,…) can be lethal
Polonium-210 colloid (a-emitter)
Concentrates in liver and spleen
Lethale dose (oral) : 50 ng
Not detectable externally
Alexander Litvinenko
Role of hospital pharmacist-no need to be a theoretical physicist!
• aseptic techniques : provide training (e.g. periodic media fill) and follow-up (similar to chemotherapy
preparation)
• check protocols (full traceability)
Specific risks of radiopharmaceuticals
Key instrument: dose calibrator
• measures the activity (Becquerel) in vials & syringes
• Usually integrated in LAF hood
• the “scale” for radiopharmaceuticals
• should be checked daily (calibration source)
The future of radiopharmaceuticals
The future of radiopharmaceuticals
Thanks for your attention!