introduction to radiopharmaceutical chemistry (lecture...

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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

2

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

4

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

5

Emission tomography - PET

Photomultiplier

BGO or LSO

Scintillator crystals

OHO

HO OH

OH

18Fββββ

++++

ββββ−−−− 180°

511 keV

511 keV


6


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


PET in drug development

and evaluation

Pharmacokinetics(Administration, distribution, elimination)

Pharmacodynamics(Drug effect on metabolism, blood flow, receptoroccupancy etc.)

Radiolabeled drug

Radiotracers (probes) + drug


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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


• “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!!!


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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


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R L R L R L



Primary tumour in the neck with lung metastesis

Therapy control

Morbus Hodgkin Lymphoma (before Chemotherapy)



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Therapy control

Morbus Hodgkin Lymphoma (after Chemotherapy)


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


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


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

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