5) Metals in Medicine (1) Inorganic Pharmaceuticals ... · 5) Metals in Medicine (13) Desinfection „Classical“ use of toxic metal ions such as +Ag , Sb3+, Sb5+ Silver sulfadiazine

1

5) Metals in Medicine (1)

Inorganic

Pharmaceuticals

Therapeutics Diagnostics

Anticancer Drugs

Pt, Ru, Au, Ti, Ga

Antiarthritis Drugs

Au

Antiulcus Drugs

Bi

Specific Drugs

Fe – High blood pressure

Ag/Sb – Anti infection

X-ray contrast agents

Ba, Gd, Dy, I

MRT contrast agents

Rare earths, Fe3+, Mn2+

Radiopharmaceuticals

I, Bi, Re Tc, I, Cr, Ga, In,

Cu

Trace elements, dietary supplements

Fe, Cu, Se, Ca, Mg, Zn

Enzyme inhibitors


Anticancer Drugs

Cis-platin

Pt

N H3

C l

C l

N H3

Mechanism of Activity

• Primarily by interaction with DNA in the

nuclei of the cells

• Coordination of {(NH3)2Pt}2+ fragments to

guanidine units

• Deformation of DNA

2


Anticancer Drugs

Cis-platin

Pt

N H3

C l

C l

N H3

Problems

• Low solubility

• Complex distribution chemistry,

• Hydrolysis in stomach, only i.v. applicable

• Unfavourable side-effects

cis -[P tC l2(NH

3)

2]

cis -[P tC l(NH3)

2(H

2O )]+cis -[P tC l(NH

3)

2(O H)]

+ C l- - C l-

+ H +

- H +

cis -[P t(NH3)

2(H

2O )

2]2+

+ C l- - C l-

cis -[P t(NH3)

2(O H)(H

2O )]+

+ H +

- H +

cis -[P t(NH3)

2(O H)

2]

+ H +

- H +

O ligom ere

pKs = 7 ,3 pK

s = 5 .6

langsam

schnell

Hydrolysis and species

oligomers

slow

fast


Anticancer Drugs

Cis-platin

Pt

N H3

C l

C l

N H3

Distribution in the body Injection

Blood

Binding to plasma proteins Transport by the bloodstream

Kidney Other organs

Excretion Liver

Tumor

Anti-cancer activity Undesired side-effects

3


Anticancer Drugs

Cis-platin derivatives

Second generation of cis-platin derivatives

• Lower dose

• Better solubility

• Less side-effects


Anticancer Drugs


Other platinum drugs under research

Pyriplatin

• Violates the ‚classical‘ structure-activity rules

• Forms monodentate DNA adducts

4


Anticancer Drugs


Novel drug delivery strategies for platinum drugs


Anticancer Drugs

Ruthenium complexes

5


Anticancer Drugs

Titanium complexes

Anticancer Drugs

Gold complexes

P P

Au

Ph

PhPh

Ph

P PPh

PhPh

Ph

+

Au

N

Cl

C l

Au

N

O

O C

C

C H3

C H3

O

O


Antiarthritis Drugs

Gold complexes

Polymeric compounds with thiolato ligands

Na O

O S O

O Na

Au

C H2

S

CH

CH2

O H

S O3Na

Au

S

O HOH

OH

OOH

Au

n

thiomalic acid thioglucose thiopropanolsulfonate

Only structurally

established compound:

Complex with thiomalic acid

6


Antiarthritis Drugs

Gold complexes

Molecular compounds

Auranofin, an orally applicable drug

• Mechanism of activity hitherto unclear

• Intracellular ligand exchange probable

• Sulphur-containing biological compounds

(gluthatione, cysteine, methionine

• Well-known metabolite: [Au(CN)2]-

S

OAcOAc

OAc

OOAc

Au P

Et

Et

Et


Antiarthritis Drugs

Gold complexes

Basic bismuth nitrate, salicylate or citrate

For treatment of inflammations of the

gastroindestinal tract

• More than 200 years history

• Treatment of gastroindestinal tract

• pH regulation and desinfection

• Mechanism mostly unclear

• Compounds: basic Bismuth(III) salts

• Hydrolysis in water and formation of hydroxo-

bridged frameworks

• Formation of polymeric layers covering the

inflamation areas

Antiulcus Drugs

Bi

Polymeric structure of Na2[Bi2(citrate)2]

Cage of

[Bi6O4(OH)4](NO3)6 · 6 H2O

7


Desinfection

„Classical“ use of toxic metal ions

such as Ag+, Sb3+, Sb5+

Silver sulfadiazine

Renewed interest by anti-malarial and anti HIV activities of

this and related compounds

Specific Drugs




Anti-malaria

Desferrioxamine

Siderophore:

Influences the Fe metabolism of

the malaria parasite

Specific Drugs



Anti HIV

Bi-cyclame derivative

Influences replication cycle of HIV

virus

Insuline mimetics

• Simple Vanadium(V) or –(IV) compounds

• Relatively less dependent on structure

• Use of less toxic complexes with organic

ligands V(IV) maltolato complex

8


• Agents with heavy atoms (Barium, Iodine, other heavy metals)

• „Classical use“: BaSO4 for X-ray studies of gastroindestinal tract

• For blood vessels: iodinated compounds, heavy metals in research

X-ray contrast agents

Ba, Gd, Dy, I, W

Iodinated compounds:

e.g.

Example: rat leg

„Normal“ X-ray Iodohexol Na6[P2W18O62]


NMR tomography

• Measurements of proton signals (H2O) in different environments

• Important parameter: relaxation behaviour of the protons (T1 and T2)

• Influence of paramagnetic compounds on T1 (shortening)

• With this, increase of the „contrast“ of the images

Paramagnetic compounds in use:

• Rare earth (mostly Gd3+) complexes

with a H2O ligand

• Mn2+ complexes

• Superparamagnetic iron oxide

nanoparticles in organic (dextrane)

layer

MRT contrast agents


9


MRT contrast agents



Research Strategies

MRT contrast agents


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Cu

Therapy

destruction of (cancer) cells

- short range

- high dose

- strongly ionising radiation

- - - emitter

- - emitter

- medium range

- low dose

- - emitter

- + - emitter

Diagnostics

Imaging of organs




Cu

- - emitter Isotope t1/2 (d) Energy (Emax, MeV) 32P 14,3 1,71 47Sc 3,4 0,6 64Cu 0,5 0,57 89Sr 50,5 1,46 90Y 2,7 2,27 102Rh 1,5 0,57 111Ag 7,5 1,05 131I 8,0 0,81 153Sm 1,9 0,8 186Re 3,8 1,07

- emitter

Isotope t1/2 (d) Energy (Emax, MeV) 211At 7,2 h 6,8 212Bi 1,0 h 7,8

- short range

- high dose

- strongly ionisating radiation

- - - emitter

- - emitter

Problem

Partially high radiations dose to

the rest of the organism

Nuclearmedical Therapy, Targeting

11




Cu

Nuclearmedical Diagnostics

- Medium range

- Low dose

- - emitter

- + - emitter

+ - Emitter

Isotope t1/2 - Energy (MeV)

11C 20,4 min 0,5 13N 9,9 min 0,5 15O 2,0 min 0,5 18F 110,0 min 0,5

- Emitter

Isotope t1/2 - Energy (MeV)

131I 8,0 d 0,36 99mTc 6,0 h 0,14

PET (Positron Emission Tomography)

SPECT (Single Photon Emission Computer Tomography)




Cu


14F 15F 16F 17F 18F 19F 20F 21F 22F 23F 24F 25F 26F 27F 28F 29F 30F 31F

proton, EC, positron (ß+) ß-

Annihilation of a positron Emission of a positron (ß+-particle)

• a positron is not stable and reacts immediately

with an electron under formation of two -quants

• transformation of matter into energy

• no ß+-spectra are measured

• instead of this, two -quants with distinct

energy ( ≈ 500 keV) can be detected (E = m c2)

• the angle between the quants is exactly 180°

PET Positron emisson tomography

12




Cu





Nuclear reaction: 18O (p,n) 18F

Target: 18O-enriched water

Proton energy: 15 - 16 MeV

Irradiation time: 2 h

Cyclotron




Cu





Glucose metabolism

18F Fluorodesoxyglucose 18F DOPA

Neurotransmitter, receptors 18F Methyltyrosin

Metabolism of amino acids

18F 5-Fluorouracil

Therapy, pharmacokinetics DNA/RNA synthesis

18F Fluorothymidin

13




Cu





Automated synthesis modul

18F FDG in isotonic saline / citrate buffer

Reaction scale: up to 10.000 GBq

Product




Cu





Classical positron emission tomograph

14




Cu


Slice images

brain myocardium tumor





Cu



Three dimensional reconstitution

15




Cu


SPECT Single Photon emisson computer tomography

SPECT with 99mTc




Cu



99mTc - as a „metastable“ nuclear isomer

99mTc

99Tc

99Mo

99mTc

99Tc

99Ru (stabil)

66h

6h

14 %

86 %

2,13 105a

16




Cu



Concentration of the 99mTc in the eluate of the generator: about 10-9 mol/l

Chemical form: pertechnetate, TcO4-

99Mo/99mTc nuclide generator




Cu



TcO4-

Thyroid scintigraphy

Asymmetrically increased thyroid gland Increased thyroid by deficiency of iodide

17




Cu






Cu



A „kit“ - vial contains:

Ligand

Reduction agent

Catalysts + Stabilisors

99mTcO4

- + „Instant Kit“ injection-ready

99mTc-pharmaceutical

Please remind ! Concentration of 99mTc: about 10-9 mol/l

Production of the injection-ready pharmaceutical directly in the clinic

18




Cu



TcO4-

Thyroid scintigraphy,

99m

Tc-pertechnetate

Kidney scintigraphy,

99m

Tc-DTPA

Liver scintigraphy,

99m

Tc-EHIDA

Bone scintigraphy,

99m

Tc-MDP

CH2

N CH2

CH2

N

CH2

COOH

CH2

COOH

CH2

N

CH2

HOOC

CH2

HOOCCH

2

COOH

N H C O C H2

N

C H2

C2H

5

C2H

5

C O OH

C H2

C O OH

O P O

O

OH

CH2

O P O

O

OH




Cu



Classical Kidney scintigraphy, 99m

Tc-DTPA

Costs: about 50€

CH2

N CH2

CH2

N

CH2

COOH

CH2

COOH

CH2

N

CH2

HOOC

CH2

HOOCCH

2

COOH

Glomerular filtration

Estimated structure of the complex

A kit vial contains e.g.:

- 20 mg DTPA

- 0.25 mg SnCl2 x 2 H2O

- 5 mg p-aminobenzoic acid

- 3.75 mg CaCl2 x 2 H2O

DRAXIMAGE® DTPA

19




Cu



Classical Liver scintigraphy, 99m

Tc-EHIDA

N H C O C H2

N

C H2

C2H

5

C2H

5

C O OH

C H2

C O OH

Costs: about 50€




Cu



Classical bone scintigraphy,

99m

Tc-MDP

O P O

O

OH

CH2

O P O

O

OH

Costs: about 50€


- 20 mg MDP

- 11 mg NaOH

- 0.13 mg SnF2

- 1 mg ascorbic acid

Braco® MDP

20




Cu



Tc(V) Complex

TcO4- +


- 0.5 mg ligand (only d,l isomer)

- 4.5 mg NaCl

- 0.0076 mg SnCl2

GE Healthcare Ceretec ®

NN

O H

N H NH

OH

O N

NN

O

N

O

H

TcSnCl2

99mTc-HMPAO (Ceretec®), brain imaging




Cu



NN

O H

N H NH

OH

99mTc-HMPAO (Ceretec®)

Costs: about 250€

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Cu



Other Tc compound for brain imaging

- Tc(V) oxo complex

- Trapping by ester

metabolism

- No stereo isomers

99mTc ECD

- Tc(V) oxo complex

- Trapping by chelate

metabolism

- No stereo isomers

99mTc MRP20

- Tc(III) complex

- Trapping by Cl-/H2O

exchange

- Not routine

BATO compound




Cu




- 1.0 mg [Cu(L)4](BF4)

- 2.6 mg sodium citrate

- 1.0 mg cysteine hydrochloride

- 20 mg mannitol

- 0.075 mg SnCl2 x 2 H2O

Brystol Myers, Squibb Cardiolite® Costs: about 250€

Tc radiopharmaceuticals for myocardial imaging

TcI

complex

22




Cu



Costs: about 250€

Tc radiopharmaceuticals for myocardial imaging

TcV complex


- 0.23 mg ligand

- 0.32 mg disodium sulphosalicylate

- 0.03 mg SnCl2

- 1.0mg sodium gluconate

- 1.8 mg NaHCO3

GE Healthcare Myoview ®




Cu



Other Tc compound for brain imaging

- Tc(V) nitrido complex

- Neutral

- Trapping by ether

metabolism

99mTc TcNNOEt

- Tc(III) complex

- Mixed-ligand

compound

- Metabolic trapping

99mTc Technecard®

- Tc(III) complex

- Neutral !!!

- Trapping by Cl-/H2O

exchange

99mTc Cardiotec®

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Cu



Radiation dose

- Mean natural radiation dose in Germany in 1999: about 2,4 mSv/a (1 -10 depending on the

geographic situation)

- Legal annual dose limit für radiation workers: 20 mSv

Nuclear medicine SPECT (99mTc) kidney function study

brain perfusion

myocardial diagnostics

thyroid

liver scintigraphy

Skeleton study

X-ray teeth images

thorax images

mammography

bile

renal tract

0,01 mSv

0,03 mSv

0,50 mSv

4,00 mSv

5,00 mSv

3 mSv

10 mSv

20 mSv

Nuclear medicine PET (18F-FDG) 7 mSv

Statistics: Bundesamt für Strahlenschutz, 2000

Nuclear medicine

PET (18F-FDG) / CT Bronchial carzinome 15 mSv Lymphome 10 mSv

Strahlenschutzkommission, 2005

CT head

CT thorax

CT gastroindestinal

1,3 mSv

2,0 mSv

3,0 mSv

1,0 mSv

4,0 mSv

4,5 mSv

Documents

5) Metals in Medicine (1) Inorganic Pharmaceuticals ... · 5) Metals in Medicine (13) Desinfection „Classical“ use of toxic metal ions such as +Ag , Sb3+, Sb5+ Silver sulfadiazine