O-(2-[18F]fluoroethyl)-L-tyrosine

[¹⁸F]FET

O-(2-[¹⁸F]fluoroethyl)-L-tyrosine

Author of the review: Ing. Helena Švecová, Ph.D.

Imaging of metabolism using PET (positron emission tomography) has enjoyed great interest for a long time. The most striking example is the wide use of [¹⁸F]FDG (2-[¹⁸F]fluoro-2-deoxy-D-glucose) in oncology, cardiology and neurology. In the diagnosis of tumour diseases using FDG-PET, the target is the increased anaerobic glycolysis that occurs in almost all types of tumour cells.

Another interesting target in tumour imaging is the increased protein metabolism and, as a result, the increased consumption of amino acids in tumour cells. Labelled amino acids can help to image tumours in those cases where the use of FDG has limited possibilities, for example when distinguishing inflammatory tissue from tumour growth or when imaging the brain.

O-(2-[¹⁸F]fluoroethyl)-L-tyrosine ([¹⁸F]FET) is an analogue of the amino acid tyrosine labelled with fluorine-18, which preferentially accumulates in brain tumours of the glioma type. Increased uptake of [¹⁸F]FET in gliomas occurs as a result of a higher occurrence of L-type amino acid transporters. However, unlike tyrosine, [¹⁸F]FET does not enter protein metabolism and is excreted from the body unchanged.

[¹⁸F]FET-PET is suitable for imaging the extent of gliomas, for guiding biopsy, for detecting tumour recurrence or for distinguishing recurrence from radiation necrosis. This information about the metabolism of [¹⁸F]FET is very useful for treatment planning, especially in combination with other imaging methods such as CT (computed tomography) or MRI (nuclear magnetic resonance). It is also a suitable tool for distinguishing tumour and inflammatory tissue.

Properties

[¹⁸F]FET is an analogue of tyrosine, to which an ethyl group with fluorine-18 is attached via an oxygen atom. The radionuclide ¹⁸F is a positron emitter with a half-life of 109.7 minutes, suitable for PET. PET using [¹⁸F]FET (FET-PET) is a suitable method for the diagnosis of brain tumours.

Pharmacokinetics

Natural tyrosine is not only a building block for proteins but also enters, as a precursor, into the synthesis of hormones, catecholamines and melanin. However, its fluorinated analogue [¹⁸F]FET has not been shown to participate in any of these processes. [¹⁸F]FET is relatively metabolically stable. It passes through the body largely unchanged and is excreted in the urine. Only a small part of [¹⁸F]FET is metabolised before excretion. The fact that [¹⁸F]FET is not involved in protein synthesis does not reduce its usefulness for detecting increased amino acid uptake in tumours.

The uptake of [¹⁸F]FET in tumours is controlled by a specific amino acid transport system. A number of experiments have shown that this is the L system. Other L-tyrosine analogues, such as L-[¹¹C]tyrosine or 2-[¹⁸F]fluoro-L-tyrosine, also use the same route for transport into the cell. Unlike them, however, [¹⁸F]FET probably uses only one subtype of the L transporter, namely LAT2. This would be indicated by the slight uptake of [¹⁸F]FET in muscle, where LAT2 is present, but zero uptake in inflammatory tissue, where LAT2 is not found.

In the whole-body distribution of [¹⁸F]FET in patients with a brain tumour, it was shown that [¹⁸F]FET is evenly distributed in the bloodstream within 20 minutes of intravenous administration and its concentration in the blood remains almost constant for a further 4 hours. [¹⁸F]FET does not accumulate in any organ more than corresponds to the perfusion of that organ. Only very slight uptake of [¹⁸F]FET appears in the muscles, pancreas and heart. In gliomas, [¹⁸F]FET reaches maximum uptake roughly 20 to 60 min after administration, with the ratio of activity in the tumour to activity in the surrounding brain tissue increasing over this interval for low-grade tumours, whereas for higher-grade tumours this ratio decreases.

Toxicity

In general, O-(2-[¹⁸F]fluoroethyl)-L-tyrosine is non-toxic and no side effects have so far been described in the literature. The toxicity of the inactive drug was verified in mice, where the highest administered dose was 150 µg/kg for 15 days. This dose was well tolerated by the animals without any problems.

The maximum activity of labelled [¹⁸F]FET administered in humans is up to 400 MBq, which, at a molecular weight of [¹⁸F]FET equal to 226.24 g/mol, corresponds to 1.43 ng of the drug, i.e. 0.02 ng/kg for a normal (70 kg) patient. Given these low administered amounts and the single clinical administration of the active substance, the risk associated with the chemical toxicity of the drug can be considered negligible.

Given the radionuclide ¹⁸F, the radiotoxicity of [¹⁸F]FET can be considered as for all diagnostic radiopharmaceuticals. 18F is a high-energy emitter (511 keV); on the other hand, its very short physical half-life (110 minutes) significantly reduces the radiation burden on the patient. When 370 MBq of [¹⁸F]FET is administered, the effective dose is 6.1 mSv, i.e. 16.5 µSv/MBq, which is within the range of routine nuclear medicine examinations (e.g. for [¹⁸F]FDG the effective dose is 27 µSv/MBq).

Use

Oncological applications

Brain tumours

[¹⁸F]FET is a suitable marker for brain tumours, as first published by H. J. Wester et al. in Munich in 1999. Further clinical and preclinical studies confirmed this finding and subsequently specified that [¹⁸F]FET can be used for the diagnosis of brain tumours of the glioma type. FET-PET is performed 30 to 60 minutes after administration of the radiopharmaceutical. Compared with the use of FDG, the images obtained from the examination have a higher contrast between tumour and normal tissue.

Before [¹⁸F]FET was discovered, two other labelled amino acids began to be used successfully for the diagnosis of brain tumours – [¹¹C]methyl-L-methionine ([¹¹C]MET) and 3-[¹²³I]iodo-α-methyl-L-tyrosine ([¹²³I]IMT). Both show very good agreement between tissue uptake and tumour extent. In comparisons with [¹¹C]MET or [¹²³I]IMT, [¹⁸F]FET shows identical properties. It has been shown that the experience with [¹¹C]MET and [¹²³I]IMT for the diagnosis of brain tumours is transferable to [¹⁸F]FET.

Another diagnostic method used to detect brain tumours is nuclear magnetic resonance (MRI). This method has a high sensitivity for detecting a tumour, but only average accuracy in determining whether it is tumour tissue or oedematous, necrotic or fibrous tissue. However, in combination with FET-PET, the accuracy increases so that it is possible to identify tumour tissue almost 100 % non-invasively, and thus better to guide biopsy or surgical intervention.

[¹⁸F]FET, like other labelled amino acids, is not suitable for tumour grading. Nevertheless, in low-grade gliomas, [¹⁸F]FET uptake of varying intensity appears. Studies show that with higher [¹⁸F]FET uptake in a glioma there is a greater probability that the tumour disease will worsen rapidly. With low to negative [¹⁸F]FET uptake, it is usually a stable glioma that may not change for many years. FET-PET appears to be a useful tool for glioma treatment planning when deciding whether or not it is necessary to use aggressive methods such as surgery or radiotherapy.

One of the problems that may be encountered in the treatment of brain tumours is the difficult distinction of tumour recurrence from radiation necrosis after treatment. FET-PET can be used to distinguish these two states. In the case of radiation necrosis, [¹⁸F]FET is taken up only weakly at the edges of the cavity after tumour resection. However, in the case of tumour recurrence, the uptake of [¹⁸F]FET is quite clearly high and concentrated at the site of the tumour.

Another possible use of [¹⁸F]FET is to distinguish tumour tissue from inflammatory tissue. Unlike [¹⁸F]FDG, but also [¹¹C]MET, [¹⁸F]FET is not taken up in macrophages or in activated microglia. This increases the specificity of [¹⁸F]FET for gliomas.

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