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Radiochemistry and Radiopharmacy III

Compact course held at UFSCAR, September 20123

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. Positron Emission Tomography (PET) with 18F Compounds..

- Isotope production with a cyclotron

- Positron radiation and PET imaging

- Principles of synthetic organic chemistry with 18F

- 18F-Desoxyglucose (FDG)

- Synthesis and use of advanced 18F radiopharmaceuticals

- Multi-method imaging

Periodic Table of Elements

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neutrons

protons

Table of nuclides (Chart of Nuclides)

neutrons

protons

Table of nuclides

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Table of nuclides

Table of nuclides

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18F as Positron Emitter

Nuclear Stability in General

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

proton, EC, positron (ß+) ß-

Nuclear Stability in General

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

proton, EC, positron (ß+) ß-

Emission of a positron (ß+-particle) - atomic number decreases by one unit - mass number remains unchanged - typical for nuclides with excess of protons - internal conversion of a proton into a neutron (+ positron + neutrino)

ß+ Decay: -  formation of a neutrino is required from the Laws of the conservation of the spin and energy -  similar process like the ß--decay -  emission of a neutrino

ν0001

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11 )()( ++→ +enucleusnnucleusp

18F as Positron Emitter

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

proton, EC, positron (ß+) ß-

Emission of a positron (ß+-particle) -  a positron is not stable and reacts immediately with an electron under formation of two γ-quants - transformation of matter into energy - no ß+-spectra are measured - instead of this, two γ-quants with distinct energy ( ≈ 500 keV) can be detected (E = m c2) - the angle between the quants is exactly 180°

Annihilation of a positron

18F as Positron Emitter

Production of 18F in a cyclotron

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

proton, EC, positron (ß+) ß-

Nuclear reaction: 18O (p,n) 18F Target: 18O-enriched water Proton energy: 15 - 16 MeV Irradiation time: 2 h

Cyclotron

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

proton, EC, positron (ß+) ß-

Cyclotron

Cyclotron centre

Production of 18F in a cyclotron

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

proton, EC, positron (ß+) ß-

H218O target

O

O

N

O

OO

N

Oionexchange + K2CO3 +

cryptant-[2,2,2]

[K(cryptant)] 18F

Fluoride separation

Nuclear properties

-  half- life: 109.7 min. -  γ-energy: 0.511 MeV

Production of 18F in a cyclotron

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Production of 18F-labelled compounds

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

proton, EC, positron (ß+) ß-

Glucose metabolism

Glucose DOPA

Neurotransmitter, receptors

Methyltyrosin

Metabolism of amino acids

Uracil

Therapy, pharmacokinetics DNA/RNA synthesis

Thymidin

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

proton, EC, positron (ß+) ß-

Glucose metabolism

18F Fluorodesoxyglucose 18F DOPA

Neurotransmitter, receptors

18F Methyltyrosin

Metabolism of amino acids

18F 5-Fluorouracil

Therapy, pharmacokinetics DNA/RNA synthesis

18F Fluorothymidin

Production of 18F-labelled compounds

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18F-Fluorodesoxyglucose (FDG)

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

proton, EC, positron (ß+) ß-

Synthesis

-  Reaction scale: up to 10.000 GBq

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

proton, EC, positron (ß+) ß-

Automated synthesis modul

18F FDG in isotonic saline / citrate buffer Product

18F-Fluorodesoxyglucose (FDG)

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

proton, EC, positron (ß+) ß-

Quality control

-  Gas chromatography: acetonitrile, EtOH

-  HPLC: residual glucose and side products

-  radiochemical purity: HPLC, TLC, certified isotope synthesis

competing nuclear reactions: 18O (p,2n) 17F (t1/2 = 64.8 sec.)

16O (p,α) 13N (t1/2 = 9.96 min) 109Cd (from silver target) 48V (spallation from Zn)

-  Sterility and endoxin (pyrogen) testing

18F-Fluorodesoxyglucose (FDG)

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

proton, EC, positron (ß+) ß-

18F as Positron Emitter -  a positron is not stable and reacts immediately with an electron under formation of two γ-quants - transformation of matter into energy - no ß+-spectra are measured - instead of this, two γ-quants with distinct energy can be detected (E = m c2) - the angle between the quants is exactly 180°

Annihilation of a positron

Positron emission tomography (PET)

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

proton, EC, positron (ß+) ß-

The principle

Positron emission tomography (PET)

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

proton, EC, positron (ß+) ß-

Classical positron emission tomograph

Positron emission tomography (PET)

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

proton, EC, positron (ß+) ß-

Slice images

brain myocardium tumor

Positron emission tomography (PET)

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

proton, EC, positron (ß+) ß-

Three dimensional reconstitution

Positron emission tomography (PET)

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

proton, EC, positron (ß+) ß-

PET/CT combination unit

Positron emission tomography (PET)

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

proton, EC, positron (ß+) ß-

PET/CT combination

Muscels and skeleton Diffuse metastases

Positron emission tomography (PET)

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

proton, EC, positron (ß+) ß-

PET/MRT combination unit

Positron emission tomography (PET)

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

proton, EC, positron (ß+) ß-

PET/MRT combination

Whole body Brain

Positron emission tomography (PET)

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

proton, EC, positron (ß+) ß-

Comparison PET / SPECT

-  „Biological“ isotopes (11C, 13N, 15O, 18F)

-  Highly resolved images

-  visualization of ‚real-time‘ biological activity

-  Too short half-lifes (20 min, 10 min, 2 min, 110 min)

-  High price (about 2.000 $ per study)

-  Frequently metals (99mTc, 111In, 131I)

-  good resolution

-  visualization of organ distribution

-  Suitable half-lifes (6 h, 2.8 d, 8 d)

-  reasonable price (150 – 300 $ per study)

Positron emission tomography (PET)

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

proton, EC, positron (ß+) ß-

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

1,3 mSv 2,0 mSv 3,0 mSv 1,0 mSv 4,0 mSv 4,5 mSv

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

CT head CT thorax CT gastroindestinal

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

German Radiation Protection Commission, 2005

Positron emission tomography (PET)

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

proton, EC, positron (ß+) ß-

Small animal PET

PET in research and development

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

proton, EC, positron (ß+) ß-

PET study in neurosciences

Society for Nuclear Medicine, 2005

PET in research and development

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

proton, EC, positron (ß+) ß-

PET scan with 18F- labelled Dopamin

PET in research and development