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- 1 -
Design of Molecular Ligands for Nuclear Imaging
Michaela Katja Möllmann
JASS 2006
Design of Molecular Ligands
for
Nuclear Imaging
- 2 -
Design of Molecular Ligands for Nuclear Imaging
Outline
I. Radiopharmaceuticals (RP)
II. Ligands as Radiopharmaceuticals (RP)
III. Design of RP Molecular Ligands
IV. Conclusion
- 3 -
Design of Molecular Ligands for Nuclear Imaging
Definition of Radiopharmaceuticals:
Radiopharmaceuticals are radioactive agents used in the field of nuclear medicine as tracers for nuclearimaging.
What are the objectives?
diagnosis therapy
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
IV. Conclusion
- 4 -
Design of Molecular Ligands for Nuclear Imaging
Nuclides for Nuclear Imaging
Fluorine 18F
Carbon 11C
Nitrogen 15N
Rhenium 188Re
Yttrium 90Y
Lutetium 177LuDosage
1 Bq (Becquerel) = one decay event per second
1 Bq = 2.7 • 10-11 Ci
5 µCi – 35 mCi
Considerationsallergy, pregnancy, breast-feeding, age, intake of othermedicine, other medical problems
Technetium 99mTc
Iodine 123I / 125I
Indium 111In
Gadolinium 67Ga
Thallium 201Tl
Krypton 81mKr
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
IV. Conclusion
- 5 -
Design of Molecular Ligands for Nuclear Imaging
I. Radiopharmaceuticals
II. Ligands as RP
Structure
Characteristics
Used Molecules
Detected Diseases
III. Design of RP Ligands
IV. Conclusion
Definition of Ligand:
In biology a ligand is an extracellular substance whichbinds in a highly specific manner to its receptor.
Definition of Receptor:
In biology a receptor is a protein on the cell membraneor within the cytoplasm or cell nucleus that binds to itsligand and initiates the cellular response to the ligand.
www.scleroderma.org
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Design of Molecular Ligands for Nuclear Imaging
receptor targetbioactivemolecule
I. Radiopharmaceuticals
II. Ligands as RP
Structure
Characteristics
Used Molecules
Detected Diseases
III. Design of RP Ligands
IV. Conclusion
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Design of Molecular Ligands for Nuclear Imaging
Binding to pathologically occuring molecules
No uptake in non-target organs/tissue
Rapid localization at target
Rapid blood-pool clearance
Uptake ~ strength of disease
Accessibility from the outside of the cell
Easy to radiolabel
Storage in kit with long shelf-life
Cheap
Reasonable dosiometry
Minimal immunological response
I. Radiopharmaceuticals
II. Ligands as RP
Structure
Characteristics
Used Molecules
Detected Diseases
III. Design of RP Ligands
IV. Conclusion
- 8 -
Design of Molecular Ligands for Nuclear Imaging
Peptide-based molecules
antibodies
Fab-fragments
scFv-fragments
affibodies
peptides
Non-peptidic
synthetic peptidomimetics
white blood cells
FabscFv
I. Radiopharmaceuticals
II. Ligands as RP
Structure
Characteristics
Used Molecules
Detected Diseases
III. Design of RP Ligands
IV. Conclusion
www.planet-wissen.dewww.biology.arizona.edu
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Design of Molecular Ligands for Nuclear Imaging
I. Radiopharmaceuticals
II. Ligands as RP
Structure
Characteristics
Used Molecules
Detected Diseases
III. Design of RP Ligands
IV. Conclusion
Tumors
Infections
Inflammations
Neurological diseases
Blood vessel diseases
Red blood cell diseases
Bone and bone marrow diseases
Diseases of several organs
.
.
.
www.muslimworld.co.uk
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Design of Molecular Ligands for Nuclear Imaging
αvβ3-antagonists
Tumor-induced angiogenesisI. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Haubner and Wester 2004
- 11 -
Design of Molecular Ligands for Nuclear Imaging
αvβ3 Integrin Antagonists
Aim: lead structure is needed
Arg1
Gly2
Asp 3
Phe4
D
-Val 5
R
G
D
hydrophobic
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
RGD-peptide
- 12 -
Design of Molecular Ligands for Nuclear Imaging
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Arg1
Gly2
Asp3
D-Phe4 D-Tyr4
Val5
Val5 Tyr5
Iodine-Labeling 125I
Haubner and Wester 2004
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Design of Molecular Ligands for Nuclear Imaging
Fluorine-Labeling 18F
Val5 Lys5
FBA = N-succinimidyl 4-[18F]-fluorobenzoate
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
FBA
Haubner and Wester 2004
a) No-carrier-added
via prosthetic groups
- 14 -
Design of Molecular Ligands for Nuclear Imaging
CH3CO218F
Fluorine-Labeling 18F
b) Carrier-added
via [18F]AcOF
AcOF = 18F-Acetylhypofluoride
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Haubner and Wester 2004
- 15 -
Design of Molecular Ligands for Nuclear Imaging
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Haubner and Wester 2004
Aim: Bioavailability
Solubility
Resistance
Val5 Lys5
D-Phe4 D-Tyr4
Glucose-basedsugar amino acid
Glucose
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Design of Molecular Ligands for Nuclear Imaging
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Val5 Lys5
Galactose-based sugar
Galactose
- 17 -
Design of Molecular Ligands for Nuclear Imaging
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Receptor specific tumor visualization via galactose-based RGD-peptide
ROI-ratio
O
HOHO OH
NH
O
18F
NH
LysD-Phe
O
HN
AspGly
ArgCO
CONH
O
HOHO OH
NH
O
18F
NH
LysD-Phe
O
HN
AspGly
ArgCO
CONH
- 18 -
Design of Molecular Ligands for Nuclear Imaging
Aim: Positive effect of hydrophilicity on
pharmacokinetic
Use of D-amino acids allows in vivo „fine tuning“I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Val5 Lys5
GABA-(D-Asp)3GABA-(D-Ser)3
Haubner and Wester 2004
- 19 -
Design of Molecular Ligands for Nuclear Imaging
111In Indium-labeling via DTPA
Val5 Lys5
DTPA = diethylenetriamine-pentaacetic acid
Haubner and Wester 2004
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
111InDTPA
Haubner and Wester 2004
- 20 -
Design of Molecular Ligands for Nuclear Imaging
99mTc-, 188Re- and 90Y-labeling via tetrapeptide orDOTA I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Haubner and Wester 2004
DOTA = 1,4,7,10-tetra-azacyclododecane-N,N',N",N'"-tetra acetic acid
Val5 Lys5
H-Asp-Lys-Cys-Lys-OHDOTA
- 21 -
Design of Molecular Ligands for Nuclear Imaging
Important: check influence of radiolabeling and modification on affinity
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Haubner and Wester 2004
Cys1
Asp2
Cys9
Cys3
Arg4Gly5
Asp6
Cys7
Phe8
HYNIC
HYNIC = hydrazinonicotinamide
- 22 -
Design of Molecular Ligands for Nuclear Imaging
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Aim: tumor accumulation
18F-labeling
99mTc-labeling
Increased affinity by introducing twoRGD motifs
H-Lys-Pro-Gln-Val-Thr-Arg-Gly-Asp-Val-Phe-Phe-Glu-Gly-NH2
H-Arg-Gly-Asp-Ser-Cys-Arg-Gly-Asp-Ser-Tyr-OH
- 23 -
Design of Molecular Ligands for Nuclear Imaging
GBHO derivativesI. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
GBHO = guanidinobenzoylhydrazino oxopentanoic acid
Iodine
Fluorine
Aim: Oral bioavailability
- 24 -
Design of Molecular Ligands for Nuclear Imaging
Cyclo RGD
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Haubner and Wester 2004
Comparison
Peptidomimetic
- 25 -
Design of Molecular Ligands for Nuclear Imaging
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Quinolone core-based
Haubner and Wester 2004
Indazole core-based
- 26 -
Design of Molecular Ligands for Nuclear Imaging
Haubner and Wester 2004
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Heterogenous Dimer
Aim: tumor accumulation
cyclo(-Arg1-Gly2-Asp3-DTyr4-Glu5-)
DTPA moiety
DTPA = diethylene-triamine-pentaacetic acid
octreotate
- 27 -
Design of Molecular Ligands for Nuclear Imaging
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Haubner and Wester 2004
Homogenous Dimer
Aim: improvement of targeting by cooperativereceptor-ligand binding glutamic
acid
cyclo(-Arg1-Gly2-Asp3-DPhe4-Lys5-)
HYNICM = 111In, 90Y, 177Lu DOTA
- 28 -
Design of Molecular Ligands for Nuclear Imaging
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Haubner and Wester 2004
modified heptaethylen glycollinker
Homogenous Multimer
Monomer
cyclo(-Arg1-Gly2-Asp3-DPhe4-Glu5-)
Haubner and Wester 2004
Diaminopropionic acidaminooxyacetate
- 29 -
Design of Molecular Ligands for Nuclear Imaging
Homogenous Multimer
Dimer
cyclo(-Arg1-Gly2-Asp3-DPhe4-Glu5-)
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Haubner and Wester 2004
Lysine-branching
- 30 -
Design of Molecular Ligands for Nuclear Imaging
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
1. Direct Labeling
2. Carbohydrates
3. Hydrophilic Tetrapeptides
4. Radiometal Labeling
5. Phage Display
6. Linear Peptides
7. Peptidomimetics
8. Hetero-/Homomultimer
IV. Conclusion
Homogenous Multimer
Tetramer
Haubner and Wester 2004
- 31 -
Design of Molecular Ligands for Nuclear Imaging
I. Radiopharmaceuticals
II. Ligands as RP
III. Design of RP Ligands
IV. Conclusion
Requirement of Lead Structure
Direct Labeling easy, but uptake of lipophilic structures by liver
Modification with Carbohydrates: no more uptake in liver
Modification with hydrophilic tetrapeptide: good tumor-to-background ratios
Radiometal-Labeling:
Uptake in kidney
Non-peptidic Substances with high affinities
Multimerization can improve tumor uptake
No gold standard
- 32 -
Design of Molecular Ligands for Nuclear Imaging
Acknowledgements
Prof. Dr. Horst Kessler
Franz Hagn
Everybody who helped organizingJASS 2006
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Design of Molecular Ligands for Nuclear Imaging
References
Kessler, H. et al. several articlesHaubner, R. and Wester, H.J., Radiolabeled Tracer for Imaging of TumorAngiogenesis and Eavaluation of Anti-Angiogenic Therapies, Current Pharmaceutical Design, 2004, Vol. 10, 1439-1455Johannsen, B. and Pietzsch, H.J., Development of technetium-99m-based CNS receptor ligands: have there been any advances? ,Springer-Verlag, 2001Kumar, V., Radiolabeled white blood cells and direct targeting of micro-organisms for infection imaging, Q J Nucl Med Mol Imaging, 2005, Vol. 49, 325-338Maecke, H.R., et al., 68Ga-Labeled Peptides in Tumor Imaging, The Journal of Nuclear Medicine, 2005, Vol. 46Steffen, A.C. et al., Affibody-mediated tumour of HER-2 expressing xenograftsin mice, Springer-Verlag, 2005Young-Seung, K. et al., A Novel Ternary Ligand System Useful for Preparation of Cationic 99mTc-Diazenido Complexes and 99mTc-Labeling of Small Biomolecules, Bioconjugate Cem, 2006, Vol. 17, 473-484
- 34 -
Design of Molecular Ligands for Nuclear Imaging
Thanks for
your
attention
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