PET Course KFSH&RC Surendra Nakka

1. PRODUCTION OF [18F] PET TRACERS:
BEYOND [18F]FDG
Surendra Nakka
Radiochemist 1, Radiopharmaceuticals Production Section
Cyclotron and Radiopharmaceuticals Department
Research Center

2. PET Radionuclides:
 Radionuclides which are being used in Positron Emission
tomography(PET) scan are called PET Radionuclides.
 Four major positron emitting Radionuclides 18F, 11C, 13N
and 15O which emits positrons(β+) are considered as
biological tracers.
Common PET Radionuclides
 Fluorine-18 is the radionuclide most often used for routine
diagnosis with PET.
Radionuclide Half life. min Decay Nuclear Reaction
18F- Fluorine 109.8 β+ 96.9, EC 3.1 18O(p,n)18F
11C- Carbon 20.3 β+ 99.8, EC 0.2 14N(p,α)11C
13N-Nitrogen 9.96 β+ 100 16O(p,α)13N
15O- Oxygen 2.2 β+ 99.9, EC 0.1 15N(p,n)15O
68Ga- Gallium 68.0 β+ 87.7 Generator

3. PET Radionuclides
 choice of radionuclide(18F) is based on ease of
production, half life and transportation.
 Emits low linear positron energy (β+ - 0.64MeV) in
tissue, leading to high resolution PET imaging.

18F can be easily substituted into biomolecules without
changing the properties of molecule or placed in a
position where its presence does not significantly alter
the biological behavior of molecule.

4. PET Radiotracers
 Radiotracer is biochemical compound tagged with PET
radionuclide, the type of PET radiotracer biodistribution in
the body provides the quantitative information using PET
images.
 [18F]FDG is currently the PET radiopharmaceutical used
routine for cancer imaging. Many alternative PET tracers
have been evaluated in preclinical and clinical studies to
characterize the tumor biology.
 PET radiotracers are class of new Radiopharmaceuticals
with high target specificity and affinity.
 New 18F labelled radiotracers have been developed that
are capable of giving more specific information, leading to
a better sensitivity and specificity

5. List of some (18F)PET radiotracers
 18F labelled PET tracers has wide applications in major
clinical areas(Oncology, Neurology and cardiology etc..)
Radiotracer Biochemical
process
PET Diagnostic
Imaging
Mechanism of uptake
[18F]FDG Glucose
metabolism
Metabolic studies Substrate for Hexokinase in
glucose metabolism
[8F]fluorocholin
e
Membrane
synthesis
Prostate, lung and
Brain tumors.
Substrate for choline kinase in
choline metabolism
[18F]FLT DNA synthesis Lymphoma Substrate for thymidine kinase
in DNA synthesis
18F]MISO,
[18F]FAZA
Hypoxia Solid tumors Intracellular reduction and
binding
[18F]FES Receptor
Binding
receptors Specific binding to estrogen
receptors
[18F]DOPA Aminoacid
transport
Parkinsons disease
and NET’s
Precursor for the synthesis of
dopamine

6.  PET tracers are designed to provide information for
preliminary diagnosis, planning radiotherapy and
evaluation of therapy.
 Fluorinated radiotracers appear to be the most attractive
option, mainly due to the wide availability of 18F and the
possibility of automated radiosynthesis.
 All new PET radiopharmaceuticals, must be manufactured
under current good manufacturing practices.
 PET radiopharmaceuticals are produced by using
automated synthesizers (GE Tracerlab MX, ORA-Neptis,
IBA- Synthra and Siemens Explora, etc..)
 Automated synthesizers can speed up synthesis time,
increase reproducibility and efficiency of radiochemistry
and reduce radiation exposure to chemists.
PET Radiotracers

7. Automated Synthesizers(PET Production)
Neptis-Perform

8. Automated Synthesizers(PET Production)
TRACERlab MX

9. Automated Radiosynthesizers
 Single platform for synthesis of many 18F radiotracers.
 Gold standard for commercial production and
distribution.
 Sterile, Disposable cassette system & prevents any cross-
contamination.
 Reproducible synthesis operation and meets cGMP
compliance/standards.
 Sep-pak purification to be used with only minor changes.
 Routine fully automated synthesis of 18F- FCH, 18F-L-
DOPA, 18F-FLT,18F-MISO,18F-FET etc…

10. 18F radiotracer production steps

11. Fluorocholine[18F-FCH]
Prepared by alkylation of DMAE with [18F]fluorobromomethane.
Synthesis steps
 Elution of [18F]fluoride - Eluent is TBA•HCO3
0.075M(Tetrabutylammonium hydrogen carbonate solution)
Aqueous solution, stabilized with ethanol.
 Evaporation of solvents and azeotropic drying @ 1200C for
11minutes.
 Labelling of Precursor - 2 steps
Primary Precursor – Dibromomethane;
Secondary precursor - Dimethylaminoethanol;

12.  Addition of Dibromomethane 100µL in 2ml AcN – Nucleophilic
fluorination of Dibromomethane at 1200C for 15min to produce
18F-Fluro bromomethane(FBM).

18F-Fluro bromomethane(FBM) is separated from
Dibromomethane by distillation over four silica sep-pak
cartridges by nitrogen flow.
 Fluoro methylation of DMAE using 18FBM on Reverse
phase[C18] sep-pak cartridge.C18 cartridge was preloaded
with 300µL of DMAE/DMSO.
 CM sep-pak cartridge is able to retain the 18F-Fluorocholine.

18F-FluoroCholine is eluted from CM cartridge using 3ml of
0.9% Nacl.

13.  Fully automated Synthesis and purification time is 45minutes
with non decay corrected Radiochemical yield of 20-25%
and no sign of radiolysis detected even after 10hr

14.  Radiochemical purity ≥ 99% ; Specific activity ≥37GBq/µmol;
pH 4.5-8.5; Kryptofix 2.2.2, ≤50µg/ml; Acetonitrile ≤410ppm;
Ethanol ≤5000ppm;DMAE ≤100ppm; CH2Br2 below detection
threshold
Kinetics of 18F-Fluorocholine- Imaging agent for prostate cancer
 Prostate cancer cells contain higher levels of choline metabolites
(e.g., phosphocholine and phosphatidylcholine) than do normal
prostate epithelial and stromal cells.
 Prostate cancer is associated with upregulated choline kinase
activity and increased choline uptake.
 The metabolic trapping of 18F-fluorocholine due to
phosphorylation by choline kinase.
 The present analogs can be used in the detection and
localization of a wide variety of neoplasmas including but not
restricted to prostate cancer, brain tumors, metastatic renal cell
carcinomas and breast, lung and colorectal tumors, melanomas
and lymphomas.

15. Fluoro-L-DOPA ([18F]-L-DOPA)
 6-Fluoro-3,4-Dihydroxy L-phenylalanine is an analogue of
large neutral amino acid L-DOPA
 [18F]-L-DOPA is a well accepted Radiotracer for the evaluation
of presynaptic dopaminergic function in Parkinson’s
disease(PD)
 Structure of [18F]-L-DOPA

16. Electrophilic or Nucleophilic substitution.
Disadvantages of Electrophilic substitution
 18F-F2 production – carrier added, low yields, needs gas
target system and expensive.
 Low specific activity of [18F]-L-DOPA and activities or yields
are not suitable for multi dose utilization.
 Time consuming HPLC Purification
 Nature of chemistry is complicated and not relaible
 Use of Organo mercuric and tin derivatives as the labelling
precursor.

17. Nucleophilic synthesis of [18F]-L-DOPA
Automated Nucleophilic synthesis of [18F]-L-DOPA is divided into
three steps: (1) Labelling
(2) Oxidation
(3) Hydrolysis and purification.
 Precursor for synthesis of Nucleophilic F-L-DOPA: (S)-3-(5-
Formyl-4-methoxymethoxy-2-nitro-phenyl)-2-(trityl-amino)-
propionic acid tert-butyl ester. (Yellowish solid)

18.  No Carrier Added 18F production by irradiation of O-18
enriched water, separation by anion exchange and elution by
TBA.HCO3
 Azeotropic distillation and nucleophilic fluorination carried
out using [18F]/TBA complex and precursor in DMSO @
temperature 950c to 1300c
 Labelled intermediate product is trapped and purified by
C18ec cartridge.
 Oxidation of intermediate product with (m-CPBA) m-
chloroperoxybenzoic acid for 15 min @ 550C.
 Hydrolysis carried out with mixture of ethanol and
hydrochloric acid @ 500c for 15 min
 After hydrolysis, the crude [18F]-L-DOPA was purified using a
reversed-phase C18/HR-P cartridge system.
 The final product eluted with citrate buffer solution to adjust
the pH and for improving stability.

19. Radiosynthesis of [18F]-L-DOPA
 The nucleophilic synthesis of [18F]-L-DOPA obtained with
>95% radiochemical purity and enantiomeric purity.
 The fully automated SPE process is reliable typical yields
are in the range of 8-12% (non-decay corrected).

20. [18F]-L-DOPA Kit configuration

21. Clinical applications of [18F]-L-DOPA
 [18F]-L-DOPA is used for the study of presynaptic striatal
dopaminergic function in neurologic disorders.
 Radiolabeled DOPA accumulates in dopaminergic
presynaptic neurons and in tumors of neuroendocrine origin.
Used to study and diagnose Parkinsonian syndromes and
for visualization of neuroendocrine tumors.
 [18F]-L-DOPA is an excellent tracer for imaging NET,
including pheochromocytoma, extraadrenal paraganglioma
(PGL), medullary thyroid carcinoma, gastro-entero-
pancreatic(GEP) NE tumors.

22. Thank you