Fludeoxyglucose (18F)

• Fluorodeoxyglucose
• Fluoro- deoxyglucose
• 18F -2 -fluoro-2 -deoxy -D-glucose
• 2-deoxy- 2-fluoro glucose
• 2- Desoxyfluorglucose
• FDG
• 2 -FDG

• 29702-43-0
• 63503-12-8 ( 18F )

V09IX04

Fixed

170-176 ° C

Attention

Only for 19F

Template: Infobox chemical / molecular formula search available

Fluorodeoxyglucose (English: fluorodeoxyglucose or fluorodeoxyglucose ) is a glucose analogue. The full name of the compound is 2-fluoro -2-deoxy -D-glucose and is usually abbreviated as FDG or 2 -FDG. Of special importance is the radioactive 18F -2 -FDG. It is the radiopharmaceutical used by far the most for the creation of a positron emission tomography (PET). It is used in cardiology, neurology and oncology for the measurement of regional glucose consumption by PET.

Natural fluorine atom to the nucleon number 19 in this case is replaced by the molecule FDG radioactive isotope fluorine-18. This isotope is a positron emitter with a half-life of only 109.8 minutes. It does not exist in nature. For the preparation of 18F -2 -FDG isotope, this is usually obtained by means of a cyclotron, for example, by bombardment of the heavy oxygen isotope 18 O with protons.

• 3.1 Suitable and non- appropriate questions
• 3.2 application
• 3.3 Radiation Exposure
• 3.4 Side Effects

Metabolism of FDG

18F -fluoro- deoxyglucose is taken up by cells of the human body such as glucose, even though a hydroxyl group has been replaced by the radionuclide 18 F of a position of the molecule. In this case, FDG is taken up by cells without energy consumption by means of glucose transporters from the blood. Currently, humans are known five of these transporters. They are referred to with Glut- 1 to Glut- 5.

The Glut- 1 is the major transport protein for the uptake of FDG in tumors and normal brain tissue. The uptake in skeletal muscle and heart muscle is stimulated by insulin and is done via the Glut-4 transporter. The enzyme hexokinase phosphorylates FDG subsequently within the cell. FDG, however, can not be further metabolized by the cells after phosphorylation. The reverse reaction, the dephosphorylation of FDG -6- phosphate to FDG occurs - with the exception of the liver - in all organs and in the tumor tissue very slowly. Therefore, there occurs accumulation of FDG -6-phosphate in the cells instead of (metabolic trapping ). Based on the decomposition of FDG 18F may be detected. The distribution of FDG in the body allows conclusions on the glucose metabolism of various tissues. This is especially for the early diagnosis of cancer of advantage as a tumor cell typically due to an increased metabolism consumes a lot of glucose and accordingly accumulate FDG. The metabolic activity of a tumor is described quantitatively by means of the SUV value.

As glucose molecule very similar FDG overcomes easily cross the blood- brain barrier. The human brain has a high demand for glucose, a correspondingly large amount of FDG is enriched in the brain. Furthermore accumulates in healthy humans FDG in the kidneys and the urinary tract.

Since 18F decays in 18O, "normal" glucose formed from FDG after the disintegration and absorption of a free hydrogen atom from the environment to form an OH group with a serious, but non-radioactive oxygen core with 0.2 % Frequency in a rare natural occurring isotope of oxygen is. The glucose formed is then metabolized in the normal way.

Possible by the decomposition of 18F -FDG imaging is an image of the distribution of glucose uptake and phosphorylation of the cells in the human body.

Synthesis

Since direct exposure to normal glucose with high-energy protons in the formation of 18F -FDG only leads to the destruction of the organic molecule, the radioactive isotope must be prepared and then processed separately using a cyclotron.

The synthesis of 2 -FDG, due to the boundary conditions

• Short half-life of 18 F,
• Radiation exposure and
• Purity and sterility of the solution for injection

Very demanding and time-consuming. Meanwhile, the preparation of 2 -FDG is largely automated. A detailed quality control, such as a plate count test is due to the short half-life, hardly possible.

For the production of 18F- 2-fluoro -2-deoxy -D-glucose, a number of possible reactions are described. In practice, two synthetic routes have proven:

• The electrophilic addition, that is the addition of double bonds at 18F -F2
• The nucleophilic substitution with 18F

The route via nucleophilic substitution is described here as an example:

Production of 18F-

In a cyclotron, a target of enriched oxygen isotope 18O with the water H218O is bombarded with high-energy protons ( 15 MeV). Here, in a nuclear reaction a small part of the 18O - oxygen is converted under each receiving a proton and the charge of a neutron in the radioactive fluorine isotope 18F. It is a positron emitter with a half-life of 109.8 minutes. 18F isotope in the aqueous phase before and 18F- fluoride ion.

Reaction with a 2 -FDG precursor

Over an ion exchanger, the fluoride formed is separated from the water and then with a solution of acetonitrile, kryptofix and potassium carbonate 222 again separated from the ion exchanger (eluted ) (2).

Nucleophilic substitution in the actual radioactive fluoride ion replaces an easily removable leaving group, such as a triflate. A suitable precursor for the preparation of 2 -FDG by means of nucleophilic substitution of 1,3,4,6 -O -acetyl-2 -O- trifluoromethanesulfonyl - β -D - mannopyranose (1), also referred to as mannose triflate. After the substitution of the triflate, the four acetyl protecting groups by basic or acidic hydrolysis with dilute sodium hydroxide or dilute hydrochloric acid is removed (4).

Purification

By reverse-phase high performance liquid chromatography (RP -HPLC), the formed 2 -FDG can be cleanly separated from the starting materials. The purification is an important step in the production of 2 -FDG in order to meet the requirements of the individual pharmacopoeias and the Good Manufacturing Practice (GMP).

Application

2 -FDG is used in PET for diagnosis, staging ( staging ), treatment and therapeutic monitoring. One speaks in this context, often of the " FDG PET".

In addition to the main application in oncology FDG for the diagnosis of Alzheimer's disease, Parkinson 's disease, Huntington's disease, epilepsy, used in cardiology and in inflammation diagnosis, but to a much lesser extent than in oncology.

Suitable and non- appropriate questions

For FDG - PET, there are three main indications for the examination of patients with oncological diseases:

• The differentiation of benign / malignant (benign / malignant) tumors,
• The tumor staging (lymph node and distant metastases) and
• The differentiation of scar tissue / vital tumor tissue ( recurrence of residual tumor).

In particular, very slow-growing tumors have usually made no substantially increased FDG uptake. An FDG- PET scan is therefore usually only in exceptional cases useful for:

• Prostate cancer,
• Differentiated neuroendocrine tumors (eg carcinoid )
• Bronchoalveolar carcinoma,
• Low -grade non -Hodgkin's lymphomas,
• Low-grade brain tumors ( astrocytoma II, oligodendroglioma II) and
• Hepatocellular carcinoma ( especially higher- differentiated forms ).

Floride inflammation and healing processes show adjacent to the tumor tissue also increased FDG uptake. An investigation into the differentiation example of abscesses and tumor tissue, sarcoidosis, lung cancer, etc., can therefore hardly be conducted properly.

As already mentioned, high blood sugar levels lead to reduced uptake of FDG in tumor tissue. When fasting blood glucose levels above 150 mg / dl therefore the indication for FDG- PET is mostly reviewed critically.

After completion of chemotherapy or radiotherapy, it is also common in viable tumor cells in a reduction of FDG uptake. Therefore should be between PET examination and completion of therapy, a period of at least four weeks. An exception are follow-up studies and certain clinical studies.

Application

In the case of full body scan in search of tumors or metastases thereof a dose of about 200 to 400 MBq, a isotonic sodium chloride solution is injected into a vein of the patient. About the body surface of the patient, the amount of activity to be administered is calculated. The target size, it is to be able to register approximately 210,000 events per layer in PET.

The patient must stay sober for at least six hours before the administration of FDG to have as low a blood sugar levels. This requirement is problematic for some diabetics, since the corresponding clinics usually do not perform PET scan when blood sugar levels above 10 mmol / l. The venous blood glucose levels are measured before each FDG- PET study.

After the injection, the patient usually has to lie for an hour in complete rest as possible without physical exercise in order to ensure the distribution of FDG in the body. Muscular effort would lead to the corresponding muscles and distort the results and can lead to artifacts in the imaging of FDG. Often observed in the region of the tongue, a strong accumulation of FDG, which is caused by frequent and severe swallowing movements of standing under extreme mental stress partially patients.

Prior to the application of water or other " calorie-free " drinks from the patient can be brought to them. Immediately before recording, the patient should empty the bladder.

Radiation exposure

The radiation dose for a PET with 2 -FDG is approximately 7-10 mSv. By comparison, the radiation dose at a contrast-enhanced computer tomography of 20-40 mSv. The amount of that dose is about twice to three times the dose of natural radiation exposure, which is exposed to an average of the European population (about 3 mSv per year). The risk of occurrence of side effects from the radiation is negligibly small for this reason. The effective dose after intravenous injection of FDG is 2.0 × 10-2 mSv / MBq. The highest radiation exposure to the bladder lies at 1.7 × 10-1 mSv / MBq.

Side effects

There are no known allergic or toxic side effects. Only the extremely low dose of injected 2 -FDG, which is in the range picomoles to nanomoles precludes this. In comparison, the quantities used in CT or magnetic resonance imaging contrast agents to move in the range of a few millimoles, which means they will be around 6-9 orders of magnitude higher.

Differentiation diagnosis - therapy

FDG is an extremely useful and well-proven compound as a diagnostic agent. The application has a purely diagnostic background. For therapy ( radiotherapy, in this particular case, one would speak of a Endoradiotherapie ) is 18F -FDG completely unsuitable radiation-type forth.

History

Tatsuo Ido from the Brookhaven National Laboratory in 1977 as first described the synthesis of 18F -FDG. The compound was injected Abass Alavi in August of 1976 from the University of Pennsylvania two volunteers. Only images of the brain, wherein the concentration of FDG in this organ was first illustrating were a normal gamma camera, a PET and not performed.