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Introduction to chemistry

(Lecture 1)

Outline

1. Introduction , Basics on , Molecular imaging, Nuclear , PET and SPECT,

2. production, , , Radionuclide generators in medicine Radionuclide generators

3. Radiometal pharmaceuticals I Radiopharmaceutical chemistry: 99m Tc-Radiopharmaceuticals, Kits

4. Radiometal pharmaceuticals II Radiopharmaceutical chemistry: Re, Cu, In, Ga, Y

5. Organic radiopharmaceuticals I Introduction to PET, 11 C-radiopharmaceuticals

6. Organic radiopharmaceuticals II 11 C-radiopharmaceuticals (continuation)

7. Organic radiopharmaceuticals III Radiofluorinations: 18 F-radiopharmaceuticals

8. Organic radiopharmaceuticals IV Radiohalogenations: Br, I, At

9. Radiopharmacology Diagnostics & Therapeutics

1 Molecular Imaging

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

Gene expression

Protein expression Protein function

Physiological function

2 Application of in life sciences

Universal, efficient, simple • High sensitivity • Studies of metabolism • Mass balance, in vivo disribution (autoradiography) • 14 C, 3H, 32 P, 35 S

Radiotracer-concept • George de Hevesey 1943 Nobel Prize (Chemistry (Application of radionuclide-based indicators, Father of )

In vivo /biochemistry • -emission-tomography (PET) • Single emission computered tomography (SPECT)  in vivo radiotracer techniques

Molecular probes and the radiotracer principle

Biochemical information

3 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)

Antibody Nuklear medicine: Tumor Antigen Use of emitters (ααα, βββ-) Iodine- 131 cell Yttrium-90 Indium-111 -186, 188

Emission tomography - SPECT

Gantry-design of a SPECT-camera

4 Emission tomography - PET

OH O 511 keV BGO or LSO HO HO OH Scintillator crystals 18F βββ+++

βββ−−− 180°

511 keV

Photomultiplier

Emission tomography - PET

5 Emission tomography - PET

Pathobiochemistry in vivo

Glycolysis Active transport Neurotransmission Multidrug resistance Hypoxia Apoptosis Angiogenesis Monitoring of gene therapy , Tumor-associated antigenes and receptors etc.

“smart “ radiotracers!

6 Selection criteria and use of molecular probes for nuclear medicine molecular imaging

• Can an appropriate compound be labeled with a suitable radionuclide? • Target specificity • High membrane permeability • Rapid clearance • No or only slow peripheral metabolism • High (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 studies

Opportunities and trends of radiopharmaceutical chemistry

• Making tumors visible as early as possible

• Better understanding of tumor biochemistry

• Therapy monitoring

7 Complex evaluation of tumor

10 13 10 12 Clinical detection

10 10

Sensitve detection

Number tumor of cells Cure 10 0

Complex evaluation

Tod

10 13 Gene expression? 10 12 Clinical detection Tumor-associated binding sites?

10 10 Metabolic activity? Apoptosis? Sensitve detection

Angiogenesis? Hypoxia?

Number tumor of cells Cure 10 0

8 Opportunities and trends of radiopharmaceutical chemistry

Molecular of neurobiological basis of cerebral function

See, how the brain is working

Opportunities and trends of radiopharmaceutical chemistry

Pharmacokinetics (Administration, distribution, elimination) Radiolabeled PET in drug development and evaluation

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

Radiotracers (probes) + drug

9 RADIOPHARMACEUTICAL CHEMISTRY

Nuclear pharmaceuticals Radiopharmaceuticals Radioactive drug

- Diagnostics (Radiotracers) - Therapeutics

Lead structure (high-throughput-screening, pathobiochemistry Target molecule

Modification: • Introduction of radionuclide • Biodistribution, pharmacokinetics (“contrast“, quantifiable, minimal burden, max. effect in

Labeling methods Radiotracer- structure

Radionuclide production

10 Important terms

Radiation and radiation energy βββ−−−, γγγ, βββ+, ααα

Radioaktivity Equation; 1 Ci = 3,7 . 10 10 Bq specific activity carrier-free, non-carrier-added, carrier-added Half-life (physical, biological, effective) Energy dose

Nuclear reactions Nuclear reactor, Cyclotron Cross-section Activation equation (n, γγγ), (p,n), (p, ααα) and (d,n)-reactions

Radiopharmaceutical chemistry Radiolabeling, radiotracer, lead structure radiochemical purity Good Manufacturing Practice (GMP)

Radiopharmacology, Nuclear medicine Dose, Target/Nontarget, Sensitivity and specificity SPET, PET, in vitro, in vivo, Perfusion, clearance, Pharmacokinetics, Pharmacodynamics

RADIOCHEMISTRY

Nuclear reactions Radionuclide production Radioaktive radiation Labeling methods Production of radiopharmaceuticals

11 RADIOCHEMISTY

Radionuclide production Processing • Nuclear reactionr • “hot“ labs • Cyclotron

Radionuclide production – Table of

12 Radionuclide production - Radioactivity

Bq Czernobyl accident 15 18 10 - 10 I-131, Xe-133, Cs-137, Kr-85, Sr-90 u.a.

Spallation 10 14 I-131, I-133/Xe-133, Mo-99/Tc-99m, Xe-135 u.a.

10 9 ectomy

10 3 K-40in adults

10 1 Cs-137/l milk in Berlin after Czernobyl

Radionuclide production

Impurities with dramatic effects

 Radiation burden

e.g. 125 I in 123 I, euthyreotic thyroid

533 mGy/MBq 125 I 5.6 mGy/MBq 123 I

1% of 125 I doubles radiation burden!!!

13 Radionuclide production

Shorter physical half-lifes plants in the clinics Iod-131 era -99m era Iod-123 (13 h)

PET era 11 C 20.4 min 14 N(p, ααα)11 C

13 N 10.0 min 16 O(p, ααα)13 N

15 O 2.0 min 14 N(d,n) 15 O

18 F 109.6 min 20 Ne(d, ααα)18 F 18 O(p,n) 18 F

Radionuclides

Diagnosis Therapy Iodine-123 Iodine-131 Technetium-99m Radiometals 3+ PET-Radionuclides … (hard M )…

C-11 F-18 I-123 Tc-99m authentic F forH, OH I forH, OH, CH 3 dramatic alterations compound Increasing availability of radionuclides

14 TcO - Iodide 4 Active transport

10 -8 - 10 -9 M Iodide 10 -1 M Chloride

- hNIS (mamma CA): TcO 4 Uptake

D. H. Moon et al., Nucl. Med. Biol. 28 (2001) 829-834

15 PET: Radiopharmaceuticals – [18 F]FDG

besonders in Hirn und OH Herz

- P nase G -6 O e xoki 18 F-D gut ität He eabil Perm tase HO spha 8 DG Pho 1 F- E G HO OH 18 F-D a Plasm Zelle in allen 18 Organen, aber H H H weniger in Hirn F HO CH2OH HO CH2OH HO CH2OH O O O und Herz H H H H H H HO HO HO OH H H H F H H H H OH OH OH

D- 2-Desoxy-D-glucose 2-Fluor-2-desoxy-D-glucose

Principle: Increased glycolysis in tumor cells (O. WARBURG) Glucose transporter (GLUT 1) and/or hexokinase Intracellular phosphorylation through hexokinase Intracellular trapping

PET: Radiopharmaceuticals – [18 F]FDG

18 F-FDG PET - Control

Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf

16 PET: Radiopharmaceuticals – [18 F]FDG

Primary tumour in the neck with metastesis

R L R L R L Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf

PET: Radiopharmaceuticals – [18 F]FDG Therapy control Morbus Hodgkin Lymphoma (before )

Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf

17 PET: Radiopharmaceuticals – [18 F]FDG Therapy control Morbus Hodgkin Lymphoma (after Chemotherapy)

Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf

Radiopharmaceuticals: 3-O-Methyl-[18 F]FDOPA

H2N CO2H Blood-brain-barrier MeO Tumour transporter HO 18F

Tumour Reference region Tumour / Brain 25000 4

3,5 20000 3

15000 2,5 2.2 2

10000 1,5

activity (Bq/ccm) 1 5000 tumour / non tumour 0,5

0 0 0 1000 2000 3000 4000 5000 Frame Midpoint Time [sec]

MRT: Surgery defect Target/Non-Target OMFD-PET

18 PET: Radiopharmaceuticals - [18 F]FDOPA

HO2C HO HO2C Decarboxylation HO NH2 NH2 NH2 HO HO HO

Tyrosine Dopa Dopamine

H2N CO2H HO

HO 18F

Control Decarboxylation disturbance Dopa to dopamine

PET: Radiopharmaceuticals - [18 F]Fluoride

O O 2+ 2+ P 3- Ca PO 4 Ca O O 2+ OH - Ca - O O 2+ 2+ Ca 3- F P PO 4 Ca O O 2+ Knochen- OH - Ca O O 2+ P Ca metastase O O

Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf

19 PET: Radiopharmaceuticals - [11 C]Acetats

Precise mechanism unclear Increased lipid metabolism

O

* ONa

Lymph node- metastasis

Rezidive

Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf

20 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 Bestrahlungszeit Aufenthaltszeit begrenzen

2. Abstand halten

3. Abschirmungen verwenden

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