radiochemistry and radiopharmacy iv...2 radiochemistry and radiopharmacy 3. single photon computer...

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Radiochemistry and Radiopharmacy IV

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 3. Single Photon Computer Tomography (SPECT) with 99mTc.

- 99mTc – Nuclear properties and production

- Nuclearmedical chemistry of technetium

- ‘Classical’ 99mTc agents for imaging of skeleton, liver, kidneys and lung

- Pharmaceuticals for brain imaging

- Pharmaceuticals for heart imaging

99mTc – Nuclear properties and production

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Isotopes and Nuclides of Technetium

Nuclide Neutrons T1/2 Decay Decay product 85Tc 42 < 110 ns ß+, p,

17 more nuclides 94Tc 51 293 min ß+ 94Mo

94mTc 51 52 min IT (0.1%), ß+ (99.9%) 94Tc, 94Mo

95Tc 52 20 h ß+ 95Mo

95mTc 52 61 d IT (3.88%), ß+ (96.12%) 95Tc, 95Mo

96Tc 53 4.28 d ß+ 96Mo

96mTc 53 51.5 min IT (98%), ß+ (2%) 96Tc, 96Mo

97Tc 54 2.6 x 106 a EC 97Mo

97mTc 54 91.4 d IT (99.7%), EC (0.3%) 96Tc, 96Mo

98Tc 55 2.6 x 106 a ß- 98Ru

98mTc 55 14.7 µs IT 98Tc

99Tc 56 2.11 x 105 a ß- 99Ru

99mTc 56 6 h IT (99.99%), ß- (0.003%) 99Tc, 99Ru

100Tc 57 15.8 s ß-, EC 100Ru, 100Mo

100m1,100m2Tc 57 8.32 s, 3.2 s IT 100Tc

101Tc 58 14.2 min ß- 101Ru

21 more nuclides 118Tc 75 > 300 ns, < 30 ms


- pure γ - emitter

- Emax = 140 KeV - no particle emission

- T1/2 = 6 h

- permanently available

(generator nuclide)

- concentration about 10-9 mol/l

- weak ß-- emitter

- Emax = 290 KeV

- T1/2 = 2,12 • 105a

- available in macroscopic

amounts

- „conventional“ chemistry

possible

99mTc 99Tc

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99mTc - as a „metastable“ nuclear isomer

99Mo

99mTc 99Tc

99Ru (stabil)

66h

6h

14 % 86 %

2,13 • 105a

99mTc

99Tc


Manufacturing of 99Mo from Uranium fuel elements

Absorption of 99Mo on a chromatography column

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Concentration of the 99mTc in the eluate of the generator: about 10-9 mol/l Chemical form: pertechnetate, TcO4

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99Mo/99mTc Nuclide generator

Nuclearmedical chemistry of technetium

TcO4-

Thyroid scintigraphy

Asymmetrically increased thyroid gland Increased thyroid by deficiency of iodide

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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


Production of the injection-ready pharmaceutical directly in the clinic

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“Classical” technetium radiopharmaceuticals

TcO4-

Thyroid scintigraphy, 99mTc-pertechnetate

Kidney scintigraphy, 99mTc-DTPA

Liver scintigraphy, 99mTc-EHIDA

Bone scintigraphy, 99mTc-MDP

CH2N CH2CH2 NCH2 COOH

CH2 COOHCH2N

CH2HOOC

CH2HOOC CH2COOH

NH CO CH2 NCH2

C2H5

C2H5

COOH

CH2 COOHO P O

O

OHCH2 O P O

O

OH


Classical Kidney scintigraphy, 99mTc-DTPA

Costs: about 70$

CH2N CH2CH2 NCH2 COOH

CH2 COOHCH2N

CH2HOOC

CH2HOOC CH2COOH

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

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Classical Liver scintigraphy, 99mTc-EHIDA

NH CO CH2 NCH2

C2H5

C2H5

COOH

CH2 COOH

Costs: about 70$


Classical bone scintigraphy, 99mTc-MDP

O P OO

OHCH2 O P O

O

OH

Costs: about 70$

A kit vial contains e.g.: -  20 mg MDP -  11 mg NaOH -  0.13 mg SnF2 -  1 mg ascorbic acid Braco® MDP

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Classical lung imaging, 99mTc-MAA (macroaggregates from albumin)

Costs: about 70$

Different principle: - Denaturated protein e.g. human serum albumin) spheres of defined size are treateded with Sn2+ - Reaction with TcO4

- gives labeled aggregates - Size of particles controls biodistribution

Tc radiopharmaceuticals for brain imaging

Basic concept (derived from classical pharmacy)

- compound must pass blood-brain barrier

- Small

- Lipophilic

- neutral

Transfer to Tc chemistry means to find a solution with coordination chemistry

-  7th group of the periodic table -  8 oxidation states -  Redox control -  Charge control by co-ligands -  ‚core‘ chemistry -  No non-radioactive isotope

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Transfer to Tc chemistry means to find a solution with coordination chemistry

+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]


Ligand Complex

TcO4- +

A kit vial contains e.g.: -  0.5 mg ligand (only d,l isomer) -  4.5 mg NaCl -  0.0076 mg SnCl2 GE Healthcare Ceretec ®

NN

OH

NH NH

OH

O N

NN

O

N

OH

TcSnCl2

99mTc-HMPAO (Ceretec®)

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NN

OH

NH NH

OH

99mTc-HMPAO (Ceretec®)

Costs: about 300$


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

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Tc radiopharmaceuticals for myocardial imaging

Basic concept (derived from classical pharmacy)

- Replacement of 201TlCl

- Cationic

- Lipophilic

- Metabolic activity for retainment

CH2 C OCH3

CH3CH3

NC

Ligand

TcI complex TcV complex

Ligand


TcI complex

A kit vial contains e.g.: -  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 300$

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TcV complex

A kit vial contains e.g.: -  0.23 mg ligand -  0.32 mg disodium sulphosalicylate -  0.03 mg SnCl2 -  1.0mg sodium gluconate -  1.8 mg NaHCO3 GE Healthcare Myoview ® Costs: about 300$

Other Tc compound for heart 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®


radiochemistry and radiopharmacy iv...2 radiochemistry and radiopharmacy 3. single photon computer...

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