Introduction to Radiopharmaceutical chemistry
(Lecture 1)
Outline
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: 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 radionuclides 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 nuclear medicine)
In vivo pharmacology/biochemistry • Positron-emission-tomography (PET) • Single photon 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: Therapy Tumor Antigen Use of particle emitters (ααα, βββ-) Iodine- 131 cell Yttrium-90 Indium-111 Rhenium-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 Inflammation, Infection 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 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 of radiopharmaceutical chemistry
• Making tumors visible as early as possible
• Better understanding of tumor biochemistry
• Therapy monitoring
7 Complex evaluation of tumor biology
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 drug 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 radiation burden, max. effect in radiation therapy
Labeling methods Radiotracer-lead 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 nuclide
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 Thyroid 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 Nuclear power plants in the clinics Iod-131 era Technetium-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-Glucose 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 lung metastesis
R L R L R L Nuklearmedizin TU Dresden / PET-Zentrum Rossendorf
PET: Radiopharmaceuticals – [18 F]FDG Therapy control Morbus Hodgkin Lymphoma (before Chemotherapy)
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 Amino acid 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
21