introduction to radiopharmaceutical chemistry (lecture...
TRANSCRIPT
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IntroductionIntroduction toto
RadiopharmaceuticalRadiopharmaceutical chemistrychemistry
((LectureLecture 1)1)
1. Introduction Radiopharmaceuticals, Basics on radiochemistry,
Molecular imaging, Nuclear medicine, PET and SPECT, Radiopharmacology
2. Radionuclide production, Nuclear reactor, Cyclotron, Radionuclide generators in medicine
Radionuclide generators
3. Radiometal pharmaceuticals I Radiopharmaceutical chemistry: 99mTc-Radiopharmaceuticals,
Kits
4. Radiometal pharmaceuticals II Radiopharmaceutical chemistry: Re, Cu, In, Ga, Y
5. Organic radiopharmaceuticals I Introduction to PET, 11C-radiopharmaceuticals
6. Organic radiopharmaceuticals II 11C-radiopharmaceuticals (continuation)
7. Organic radiopharmaceuticals III Radiofluorinations: 18F-radiopharmaceuticals
8. Organic radiopharmaceuticals IV Radiohalogenations: Br, I, At
9. Radiopharmacology Diagnostics & Therapeutics
Outline
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Molecular imaging of specific biological and physiological processes at the molecular
level in the intact organism
Optical imaging Radionuclide-based imaging
“Making the body biochemically transparent“
Molecular Imaging
Molecular Imaging
Geneexpression
Proteinexpression
Protein
function
Physiologicalfunction
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Universal, efficient, simple• High sensitivity• Studies of metabolism• Mass balance, in vivo disribution (autoradiography)• 14C, 3H, 32P, 35S
Radiotracer-concept• George de Hevesey
1943 Nobel Prize (Chemistry(Application of radionuclide-based indicators, Father of nuclear medicine)
In vivo pharmacology/biochemistry• Positron-emission-tomography (PET)• Single photon emission computered tomography (SPECT)���� in vivo radiotracer techniques
Application of radionuclides in life sciences
Molecular probes and the radiotracer principle
Biochemicalinformation
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Radionuclides in medicine – Nuclear medicine
Nuclear medicine:Diagosis
Use of gamma- and positron emitters
Sensitivity = right positive/(right positive + false negative)
Specificity = right negative/right negative + false positive)
Nuklear medicine: Therapy
Use of particle emitters (αααα, ββββ-)Iodine- 131
Yttrium-90
Indium-111
Rhenium-186, 188
Tumor
cell
Antigen
Antibody
Emission tomography - SPECT
Gantry-design of a SPECT-camera
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Emission tomography - PET
Photomultiplier
BGO or LSO
Scintillator crystals
OHO
HO OH
OH
18Fββββ
++++
ββββ−−−− 180°
511 keV
511 keV
Emission tomography - PET
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Emission tomography - PET
Pathobiochemistry in vivo
Glycolysis
Active transport
Neurotransmission
Multidrug resistance
Hypoxia
Apoptosis
Angiogenesis
Monitoring of gene therapy
Inflammation, Infection
Tumor-associated antigenes and receptors
etc.
“smart “ radiotracers!
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SelectionSelection criteriacriteria and and useuse of of molecularmolecular probesprobes
forfor nuclearnuclear medicinemedicine molecularmolecular imagingimaging
• Can an appropriate compound be labeled with a suitable radionuclide?
• Target specificity
• High membrane permeability
• Rapid blood clearance
• No or only slow peripheral metabolism
• High specific activity (Radiotracer principle)
• Low non-specific binding (Target-to-Non-target ratio >>1)
• Only a limited number of transport and biochemical reaction steps to
facilitate tracerkinetic modelling
1. Molecular probes based upon enzyme-mediated transformations
2. Molecular probes based upon stochiometrical binding interactions
3. Molecular probes for perfusion studies
Opportunities and trends ofradiopharmaceutical chemistry
• Making tumors visible as
early as possible
• Better understanding of
tumor biochemistry
• Therapy monitoring
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Complex evaluation of tumor biology
100
1013
1012
1010
Nu
mb
er
of
tum
or
ce
lls Clinical detection
Sensitve detection
Cure
Complex evaluation
100
1013
1012
1010
Tod
Apoptosis?
Gene expression?
Tumor-associatedbinding sites?
Hypoxia?Angiogenesis?
Metabolic activity?
Nu
mb
er
of
tum
or
ce
lls Clinical detection
Sensitve detection
Cure
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Molecular of
neurobiological basis of
cerebral function
See, how the brain is
working
Opportunities and trends ofradiopharmaceutical chemistry
PET in drug development
and evaluation
Pharmacokinetics(Administration, distribution, elimination)
Pharmacodynamics(Drug effect on metabolism, blood flow, receptoroccupancy etc.)
Radiolabeled drug
Radiotracers (probes) + drug
Opportunities and trends ofradiopharmaceutical chemistry
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RADIOPHARMACEUTICAL CHEMISTRY
Nuclear pharmaceuticals
RadiopharmaceuticalsRadioactive drug
- Diagnostics (Radiotracers)
- Therapeutics
Lead structure(high-throughput-screening, pathobiochemistry
Radiotracer-lead structure
Target molecule
Labeling methods
Radionuclide production
Modification:
• Introduction of radionuclide• Biodistribution, pharmacokinetics
(“contrast“, quantifiable,
minimal radiation burden, max.
effect in radiation therapy
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Important terms
Radiation and radiation energy
ββββ−−−−, γγγγ, ββββ+, αααα
Radioaktivity
Equation; 1 Ci = 3,7 . 1010 Bq
specific activity
carrier-free, non-carrier-added, carrier-addedHalf-life (physical, biological, effective)
Energy dose
Nuclear reactions
Nuclear reactor, CyclotronCross-section
Activation equation
(n,γγγγ), (p,n), (p,αααα) and (d,n)-reactions
Radiopharmaceutical chemistryRadiolabeling, radiotracer, lead structure
radiochemical purity
Good Manufacturing Practice (GMP)
Radiopharmacology, Nuclear medicineDose, Target/Nontarget, Sensitivity and specificity
SPET, PET,
in vitro, in vivo,
Perfusion, clearance, Pharmacokinetics, Pharmacodynamics
RADIOCHEMISTRY
Nuclear reactionsRadionuclide production
Radioaktive radiationLabeling methodsProduction of radiopharmaceuticals
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RADIOCHEMISTY
Radionuclide production
• “hot“ labs• Nuclear reactionr
• Cyclotron
Processing
Radionuclide production – Table of nuclide
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K-40in adults
Czernobyl accident
I-131, Xe-133, Cs-137, Kr-85, Sr-90 u.a.
Thyroid ectomy
Spallation
I-131, I-133/Xe-133, Mo-99/Tc-99m, Xe-135 u.a.
Cs-137/l milk in Berlin after Czernobyl
Bq
101
103
109
1014
1015 - 1018
Radionuclide production - Radioactivity
Impurities with dramatic effects
� Radiation burden
e.g. 125I in 123I, euthyreotic thyroid
533 mGy/MBq 125I5.6 mGy/MBq 123I
1% of 125I doubles radiation burden!!!
Radionuclide production
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Radionuclide production
Nuclear power plants in the clinics
11C 20.4 min 14N(p,αααα)11C
13N 10.0 min 16O(p,αααα)13N
15O 2.0 min 14N(d,n)15O
18F 109.6 min 20Ne(d,αααα)18F18O(p,n) 18F
Iod-131 era
Iod-123 (13 h)
PET era
Shorter physical half-lifes
Technetium-99m era
Radionuclides
C-11 F-18 I-123 Tc-99m
authentic F for H, OH I for H, OH, CH3 dramatic alterationscompound
Iodine-123
Technetium-99m
PET-Radionuclides…
Diagnosis Therapy
Iodine-131
Radiometals(hard M3+)…
Increasing availability of radionuclides
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10-8 - 10-9 M Iodide10-1 M Chloride
Active transportTcO4- Iodide
hNIS (mamma CA): TcO4- Uptake
D. H. Moon et al., Nucl. Med. Biol. 28 (2001) 829-834
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besonders
in Hirn und
Herz
D-Glucose 2-Desoxy-D-glucose 2-Fluor-2-desoxy-D-glucose
in allen
Organen, aber
weniger in Hirn
und Herz
Hexokinase
Phosphatase
Zelle
E
OH
H
HOH
OH
H
O
OH
HH
CH2OH
OH
H
HOH
OH
H
O
H
HH
CH2OH
OH
H
HOH
OH
H
O
F
HH
CH2OH
gute
Permeabilität
18F-DG 18F-DG
18F-DG-6- P
Plasma
PET: Radiopharmaceuticals – [18F]FDG
Principle: Increased glycolysis in tumor cells (O. WARBURG)
Glucose transporter (GLUT 1) and/or hexokinase
Intracellular phosphorylation through hexokinase
Intracellular trapping
OHO
HO OH
OH
18F
18F-FDG PET - Control
Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf
PET: Radiopharmaceuticals – [18F]FDG
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R L R L R L
Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf
PET: Radiopharmaceuticals – [18F]FDG
Primary tumour in the neck with lung metastesis
Therapy control
Morbus Hodgkin Lymphoma (before Chemotherapy)
Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf
PET: Radiopharmaceuticals – [18F]FDG
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Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf
Therapy control
Morbus Hodgkin Lymphoma (after Chemotherapy)
PET: Radiopharmaceuticals – [18F]FDG
Radiopharmaceuticals: 3-O-Methyl-[18F]FDOPA
MRT: Surgery defect OMFD-PETTarget/Non-Target
0
5000
10000
15000
20000
25000
0 1000 2000 3000 4000 5000
Frame Midpoint Time [sec]
ac
tiv
ity
(B
q/c
cm
)
0
0,5
1
1,5
2
2,5
3
3,5
4
tum
ou
r /
no
n t
um
ou
r
Tumour Reference region Tumour / Brain
2.2
Blood-brain-barrier
Amino acid
transporter
Tumour
MeO
HO 18F
H2N CO2H
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Control Decarboxylation disturbanceDopa to dopamine
HO
HO 18F
H2N CO2H
HO
NH2
HO2C
HO
NH2
HO2CHO
HO
NH2
HO
Tyrosine Dopa Dopamine
Decarboxylation
PET: Radiopharmaceuticals - [18F]FDOPA
PET: Radiopharmaceuticals - [18F]Fluoride
Knochen-
metastase
Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf
OP
O
OO
OP
O
OO
OP
O
OO
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
OH-
PO43-
PO43-
OH-
F-
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PET: Radiopharmaceuticals - [11C]Acetats
Rezidive
Lymph node-
metastasis
Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf
ONa
O
*
Precise mechanism unclear
Increased lipid metabolism
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Strahlenschutz – Gesamte Strahlenexposition
Radiation protection
5-A-Regel
• Begrenzung der eingesetzten Aktivität
• Aufenthaltszeit begrenzen - Verringerung der Bestrahlungszeit
• Abstand halten
• Abschirmungen verwenden
• Aufnahme von radioaktiven Stoffen vermeiden (bei Umgang mit
offenen Radionukliden)
Kombination von Strahlenschutzmaßnahmen
1. Verringerung der BestrahlungszeitAufenthaltszeit begrenzen
2. Abstand halten
3. Abschirmungen verwenden