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]



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


Biomimetic Approach Direct Labeling

Biomolecule

M

Bifunctional Approach

Biomolecule

Spacer

M

O

NRe

S

S

N O

O

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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


Biomimetic Approach

Progesterone

N

O

Re

S

S

NO

O

O

O „Re mimic“

-  relatively low receptor affinity

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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


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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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-


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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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


Direct Labeling

Peptide TcO4-

Reduction

The [Tc(CO)3]+ core and its preference for aromatic amines

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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


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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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



Receptor binding molecules (Dopamine transporter

Davison, Jones et al., Synapse, 1999

MR tomogramme 99mTc SPECT Co projection

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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



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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Possible pentadentate ligand systems for bioconjugation




Possible pentadentate ligand systems for bioconjugation


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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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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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Ligands for 68Ge pharmaceuticals

A recent bioconjugation example for 68Ga (M. Eisenhut, Bioorg. Med. Chem. 20 (2012) 1502.)

radiochemistry and radiopharmacy v...compact course held at ufscar, september 2013 ulrich abram...

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