radiochemistry and radiopharmacy v...compact course held at ufscar, september 2013 ulrich abram...
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Radiochemistry and Radiopharmacy V
Compact course held at UFSCAR, September 2013
Ulrich Abram Freie Universität Berlin Institute of Chemistry and Biochemistry
Radiochemistry and Radiopharmacy 1. Fundamentals of Radiochemistry. 2. Radiation and Biology. Basics in Nuclearmedical Diagnostics and Therapy. 3. Positron Emission Tomography (PET) with 18F Compounds. 4. Single Photon Computer Tomography (SPECT) with 99mTc. 5. Nuclearmedical Research for Diagnostics (99mTc, 68Ga) and Therapy (186Re, 188Re).
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Radiochemistry and Radiopharmacy 4. Nuclearmedical Research for Diagnostics (99mTc, 68Ga) and Therapy (186Re, 188Re).
- Technetium and rhenium ‘cores’
- 99Tc chemistry
- Synthetic approaches for the labeling of biomolecules
- Related rhenium chemistry and ligand design
- Is 68Ga a potential substitute for 99mTc?
Technetium and technetium ‘cores’
3
+7
+6
+5
+4
+3
+2
+1
0 TcO4
- Tc metal reduction oxidation
[Tc2(CO)10]
[TcH9]2-
[TcCl6]2-
[TcOCl4]- [Tc(C6H6)2]+
[TcBr4]2-
[Tc(tmbt)3(MeCN)2]
[Tc(abt)3]
Technetium and technetium ‘cores’
Technetium and technetium ‘cores’
Tc(VII) Tc(VI) Tc(V) Tc(IV) none Tc(III) Tc(II) Tc(I)
Technetium ‚cores‘
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99Tc chemistry
TcO4-
[TcVOCl4]-
[TcVINCl4]-
[TcIVCl6]2-
[TcII(NO)Cl4]-
[TcI(CO)3Cl3]2-
conc.HCl, NaN3, Reflux
conc.HCl r.t.
conc.HCl, Reflux
conc.HCl, NH2OH, RT
conc. HCl, CO, BH3, reflux
Nitrido Core
Monooxo Core Nitrosyl Core
Tricarbonyl Core
99Tc chemistry
Nuclear Properties
- weak ß-- emitter
- Emax = 290 KeV
- t1/2 = 2.12 • 105a
- available in macroscopic
amounts
- „conventional“ chemistry is
possible
99Tc
Physical and chemical Properties
- Common transition metal
- Macroscopic amount → X-Ray
- Various oxidation states
- diamagnetic → NMR
- paramagnetic → EPR
- redox chemistry → CV
- Nuclear spin 9/2 → 99Tc NMR
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Tc(VII) Tc(VI) Tc(V) Tc(IV) none Tc(III) Tc(II) Tc(I)
99Tc chemistry
Specific ligand design becomes important - Donor atom set must stabilise oxidation state - Donor atom constallation must complete core - ‚bite‘ angles must provide optimal chelate
stabilisation - Redox chemistry must be minimised
Tc(VII)
99Tc chemistry
Trioxotechnetium(VII) core - ‚Hard‘ donor atoms - Facial coordination - Mononegativ, when neutral complexes are intended - Neutral, when cationic complexes are intended
Example:
Ligand
Inorg. Chem. 45 (2006) 6589
Synthesis Product
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Tc(V)
99Tc Chemistry
Oxotechnetium(V) cores - ‚Soft‘ or ‚medium‘ donor atoms - Planar or five-coordinate ligands
Examples:
Inorg. Chem. 42 (2003) 6160 H.H. Nguyen, Thesis, FU Berlin, 2009 Chem. Commun. (1990) 1772
Tc(V)
99Tc Chemistry
Oxotechnetium(V) cores - ‚Soft‘ or ‚medium‘ donor atoms - Planar or five-coordinate ligands
Examples:
Inorg. Chem. 42 (2003) 6160 H.H. Nguyen, Thesis, FU Berlin, 2009 Chem. Commun. (1990) 1772
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99Tc Chemistry
Challenge: Synthesis of the ligands
H.H. Nguyen, Thesis, FU Berlin, 2009
Tc(I)
99Tc Chemistry
Tricarbonyltechnetium(I) core - ‚Soft‘ or ‚medium‘ donor atoms - Facial coordination
Examples:
Polyhedron 40 (2012) 153
Ligand Complex Comparison 99Tc/99mTc by HPLC
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Synthetic approaches for the labeling of biomolecules
- Functional tracers - Labeling of biomolecules (proteins, peptides, receptor binding molecules)
- high (quantitative) yield
- high purity
- no purification steps
- fast synthesis
- formation of inert products
- no parallel reactions
- no exchange reactions
- in vivo stability
- preservation of the functionality
of the biomolecule
Synthetic approaches for the labeling of biomolecules
Biomimetic Approach Direct Labeling
Biomolecule
M
Bifunctional Approach
Biomolecule
Spacer
M
O
NRe
S
S
N O
O
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Synthetic approaches for the labeling of biomolecules
Modeling of physicochemical and/or topological properties of bioactive molecules
N
O
Re
S
S
NO
O
O
O
Structures of steroid hormones (5- and 6-membered rings) are adopted by chelate rings of technetium complexes
Biomimetic Approach
Katzenellenbogen et al., J. Med. Chem. 1994
Synthetic approaches for the labeling of biomolecules
Biomimetic Approach
Progesterone
N
O
Re
S
S
NO
O
O
O „Re mimic“
- relatively low receptor affinity
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Synthetic approaches for the labeling of biomolecules
Biomimetic Approach
- General problem: octahedral or square pyramidal coordination spheres of the metal atoms
N
O
Re
S
S
NO
O
- Probable solution: - Tc or Re complexes in tetrahedral environment - requires Tc(VII)/Re(VII) chemistry and/or organometallic chemistry
Synthetic approaches for the labeling of biomolecules
Biomolecule
M
Main Problem - Preservation of the functionality
of the biomolecule
- Use of inert complexes
- Specific labeling positions must
be targeted
Direct Labeling
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Synthetic approaches for the labeling of biomolecules
J. Am. Chem.Soc. 120 (1998) 7987
Direct Labeling
Cl
Tc
COOC CO
ClCl
2- OH2
Tc
COOC CO
OH2H2O
+
< 2 M in Cl-
stable 0 < pH < 14
Organometallic approach with tricarbonylrhenium(I) and –technetium(I) complexes
TcO4- + CO + HCl + BH3 x THF [Tc(CO)3Cl3]2-
Synthetic approaches for the labeling of biomolecules
Re
Br
CO
S
OC
OC
N
NH2
NH
Re
Br
COOC
OC
NH
N
NH
N
Re
O
CO
O
OC
O
CO
PP PRO OR
ROOR RO
ORCo
Re
COOC
OC S
O
C
C
Br
NH
Ph
NEt Et
Re
COOC
OC NH2
O
HN
N
O
Re
Br
CO
Br
OC
OC
Br
N
Re
COOC
OC O
PPh2
Cl
Re
COOC
OC NH
S
N
OCCO
CO
SS S
Re
Fe
2- +
R = Me, Et
NaL L
HL
HL
2 L
LLL
Coord. Chem Rev. 190 (1999) 901
Direct Labeling
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Synthetic approaches for the labeling of biomolecules
Direct Labeling
Imidazole Histamine Histidine
[Tc(CO)3(Im)3]+ [Re(CO)3Br(Histamin)] [Tc(CO)3(Histidin]
The [Tc(CO)3]+ core and its preference for aromatic amines
Synthetic approaches for the labeling of biomolecules
Direct Labeling
Peptide TcO4-
Reduction
The [Tc(CO)3]+ core and its preference for aromatic amines
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Synthetic approaches for the labeling of biomolecules
Direct Labeling
Problems during direct labeling of antibodies: - Reduction of disulfide bridges - Formation of thiolato complexe of undefined compositions
S-S
S Tc SN
NHN
NHN
NH
HN
N
HN
N
scFv
Synthetic approaches for the labeling of biomolecules
Direct Labeling
[99mTcO4]-
[99mTc(OH2)3(CO)3]+
scFv-[99mTc(CO)3]
scFv 20 - 37°C, 30 min 1mg / ml
General labeling Method !!
A (his)n-tag is a strong bonding site for [fac-Tc(CO)3]+
Nature, Biotechnology 17 (1999) 897
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Synthetic approaches for the labeling of biomolecules
Bifunctional Approach
Spacer Biomolecule
M
Chelator
Steroid hormones
O
NRe
S
S
N O
O
HO
N
RePh3P PPh3
Cl ClCl
O
SO
Re
SCO
Br
COCO
Kung et al., Nucl. Med. Biol., 2001
Arterburn et al., Angew. Chem. 1996
Johannsen et al., Nucl. Med. Biol, 1996
Synthetic approaches for the labeling of biomolecules
Bifunctional Approach
Receptor binding molecules (Dopamine transporter
Davison, Jones et al., Synapse, 1999
MR tomogramme 99mTc SPECT Co projection
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Synthetic approaches for the labeling of biomolecules
Bifunctional Approach
Bioconjugation Approaches
Problems with the in vivo stability of the compounds (exchange reactions with plasma proteins) favour bioconjugation systems with tridentate or higher chelate systems
Synthetic approaches for the labeling of biomolecules
Bifunctional Approach
Possible tetradentate ligand systems for bioconjugation
N-terminus of proteins N-terminus of proteins ‚Click‘ reactions with azide-substituted proteins
J.D. Castillo Gomez, MasterThesis, FU Berlin, 2011
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Synthetic approaches for the labeling of biomolecules
Bifunctional Approach
Possible pentadentate ligand systems for bioconjugation
H.H. Nguyen, Thesis, FU Berlin, 2009
Synthetic approaches for the labeling of biomolecules
Bifunctional Approach
Possible pentadentate ligand systems for bioconjugation
H.H. Nguyen, Thesis, FU Berlin, 2009
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186Re and 188Re as potential therapy nuclides
186Re 188Re
- ß- - emitter - strong particle radiation
Emax = 137 keV Emax = 155 keV T1/2 = 3.8 d T1/2 = 17 h generator nuclide
Coordination chemistry of Re is similar to that of Tc Synergy
Is 68Ga a potential substitute for 99mTc?
68Ga
- Mixed positron/electron capturing emitter - Positron emitter without cyclotron !!! - Generation from 58Ge/68Ga generator
- Suitable for PET imaging
E = 1.9 MeV T1/2 = 67.6 min.
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Is 68Ga a potential substitute for 99mTc?
Production of 68Ge 69Ga + p+ → 68Ge + n Cyclotron reaction
68Ge/68Ga generator 68Ge → 68Ga + e+ elution mit diluted HCl
Is 68Ga a potential substitute for 99mTc? Ligands for 68Ge pharmaceuticals
- Mainly derivatives of DOTA (1,4,7,10- tetraazacyclododecan-1,4,7,10-tetraacedic acid
- More complex coordination chemistry is still to be developed - Allows bioconjugation
- Has serious potential to accompany or even to replace 99mTc
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Is 68Ga a potential substitute for 99mTc?
Ligands for 68Ge pharmaceuticals
A recent bioconjugation example for 68Ga (M. Eisenhut, Bioorg. Med. Chem. 20 (2012) 1502.)