# Fluoroethyl-L-tyrosine (18F)

Fluoroethyl-l-tyrosine ($^{18}$F) commonly known as [$^{18}$F]FET, is a radiopharmaceutical tracer used in positron emission tomography (PET) imaging. This synthetic amino acid, labeled with the radioactive isotope fluorine-18, is a valuable radiopharmaceutical tracer for use in neuro-oncology for diagnosing, planning treatment, and following up on brain tumors such as gliomas. The tracer's ability to provide detailed metabolic imaging of tumors makes it an essential tool in the clinical management of brain cancer patients. Continued advancements in PET imaging technology and the development of more efficient synthesis methods are expected to further enhance the clinical utility of [$^{18}$F]FET.

## Radiosynthesis

There are two common pathways for the radiosynthesis of [$^{18}$F]FET. The first one utilizes a nucleophilic $^{18}$F-fluorination of ethyleneglycol-1,2-ditosylate with a subsequent $^{18}$F-fluoroethylation of a precursor di-potassium salt of L-tyrosine. This sequence requires two purification steps, two different precursors and a dual-reactor synthesis module which is not widely available in research or commercial centers. Schematic for this pathway is presented in Figure 1.
Second route of radiosynthesis is a direct nucleophilic $^{18}$F-fluorination a TET (O-(2-tosyloxy-ethyl)-N-trityl-L-tyrosine tertbutylester) pretected precursor followed by acidic hydrolysis of protecting groups. Schematic for this pathway is presented in Figure 2.

## Mechanism of action

The use of radiolabeled amino acids for brain tumor imaging utilizes the increased proiliferation of tumor cells and overexpression in the amino acid transport system observed in malignant brain tumors.
As far as the [$^{18}$F]FET is concerned following intravenous injection it is transported into cells primarily through amino acid transporters, particularly system L transporters, which are upregulated in many tumor cells. Once inside the cells, [$^{18}$F]FET does not undergo significant further metabolism but accumulates in tumor tissues, allowing for their visualization and quantification using PET imaging.
The differential uptake provides a high tumor-to-background contrast, facilitating the detection of primary and recurrent brain tumors. Unlike some other PET tracers, [$^{18}$F]FET does not significantly accumulate in inflammatory tissues, reducing false positives and improving diagnostic specificity.

## Animal studies

Animal studies in rodents have demonstrated high uptake of [$^{18}$F]FET in brain tumors, with a significant tumor-to-brain ratio, making it a useful tracer for brain tumor imaging.
Heiss et al. conducted in vitro and in vivo investigation of transport mechanism and uptake of [$^{18}$F]FET. The experimented utilized human colon carcinoma cells (SW 707) and xenotransplanted, tumor-bearing mice. [$^{18}$F]FET was shown to be transported mainly (>80%) by the l-type amino acid transporter system, which was inhibited by 2-amino-2-norbornanecarboxylic acid (BCH) and not incorporated into proteins in SW 707 cells. This study also help to establish the half-life of [$^{18}$F]FET in the plasma (94 min), brain-to-blood ratio (0.86) and shower statistically significant higher uptake of [$^{18}$F]FET in the xenotransplanted tumor than in any other organ beside the pancreas.
In 1999 biodistribution studies in mice with colon carcinoma cells were conducted by Wester et al. The study showed a high uptake of radioactivity in the pancreas (18% injected dose (ID)/g) at 60 min after injection of [$^{18}$F]FET. The brain (2.17% ID/g) and the tumors (6.37% ID/g) showed moderate uptakes of the radiotracer. Rapid distribution of [$^{18}$F]FET with completion time of less than 5 min was observed for liver, kidney and blood. The other organs showed little elevated uptake with time. [$^{18}$F]FET remained intact in the tissue tested samples (pancreas, brain, tumor and plasma) and no incorporation of radiotracer into proteins was observed.
Another biodistribution study was carried out by Wang et al. In this study the comparison between [$^{18}$F]FDG and [$^{18}$F]FET in rats with gliomas showed a moderate uptake and a long retention time of [$^{18}$F]FET in liver, kidneys, lung, heart and blood whereas a diminished uptake was observed in healthy brain. The maximum uptake of [$^{18}$F]FET and [$^{18}$F]FDG in the glioma was observed at 60 min post injection 1.49% and 2.77% ID/g, respectively. The tumor-to-brain ratios were 3.15 for [$^{18}$F]FET and 1.44 for [$^{18}$F]FDG. PET images of [$^{18}$F]FET showed higher uptake and better contrast for tumor vs health tissue.
Biodistribution studies in mice and rats have shown that [$^{18}$F]FET is retained in tumor tissues and exhibits low uptake in inflammatory tissues, enhancing its specificity for tumor imaging. In vivo experiments have also indicated that [$^{18}$F]FET can effectively differentiate between high-grade and low-grade tumors based on the level of tracer uptake. Additionally, longitudinal studies in animal models have shown that [$^{18}$F]FET PET imaging can be used to monitor tumor progression and response to therapy, providing valuable insights into the efficacy of treatment regimens. These preclinical findings have laid the groundwork for the successful translation of [$^{18}$F]FET PET imaging into clinical practice.

## Medical use

[$^{18}$F]FET radiotracer has several clinical applications, particularly in neuro-oncology:
* Diagnosis of Brain Tumors - [$^{18}$F]FET is used to differentiate between malignant and benign brain lesions. It is particularly useful in identifying gliomas, which typically exhibit high [$^{18}$F]FET uptake.
* Tumor Grading - intensity of [$^{18}$F]FET uptake provides insights into the aggressiveness of the tumor. Higher uptake values are often associated with higher tumor grades and more aggressive behavior.
* Treatment Planning - [$^{18}$F]FET PET imaging assists in delineating tumor boundaries more accurately than conventional imaging modalities, crucial for planning surgical resection or radiotherapy to ensure maximal tumor removal while sparing healthy tissue.
* Monitoring Treatment Response - by comparing pre- and post-treatment scans, clinicians can assess the effectiveness of therapeutic interventions. A decrease in [$^{18}$F]FET uptake post-treatment might indicate a positive response.
* Detection of Recurrence - [$^{18}$F]FET is effective in distinguishing between tumor recurrence and post-treatment changes such as radiation necrosis, critical for appropriate clinical management.

## Dosimetry

Initial [$^{18}$F]FET dosimetry was estimated by Pauleit et al. based on human dynamic PET scans after injection of 400 MBq of radiotracer at 70 and 200 min. The highest dose was received by bladder (0.060 mGy/MBq) and subsequently by kidneys (0.020 mGy/MBq) and uterus (0.022 mGy/MBq). No increased uptake was observed in the liver, bone, intestine, lung, heart, or pancreas. The effective dose determined by human study was 0.0165 mSv/MBq whereas the effective dose based on biodistribution data of mice was estimated to be 0.009 mSv/MBq.
Recommended activity dose for and adult (weight 70 kg) is in the range of 180 to 250 MBq.
Based on the Radiation Dose to Patients from Radiopharmaceuticals (4th addendum) the absorbed doses in human organs are presented in the table below.
| Organ | Absorbed dose per unit activity administered [mGy/MBq] | Absorbed dose per unit activity administered [mGy/MBq] | Absorbed dose per unit activity administered [mGy/MBq] | Absorbed dose per unit activity administered [mGy/MBq] | Absorbed dose per unit activity administered [mGy/MBq] |
| Organ | Adults | 15 y | 10 y | 5 y | 1 y |
| Adrenals | 0.014 | 0.017 | 0.026 | 0.042 | 0.077 |
| Bladder | 0.085 | 0.11 | 0.16 | 0.22 | 0.30 |
| Brain | 0.013 | 0.013 | 0.021 | 0.034 | 0.064 |
| Breasts | 0.0095 | 0.012 | 0.018 | 0.030 | 0.057 |
| Gall bladder | 0.014 | 0.017 | 0.026 | 0.038 | 0.068 |
| Stomach | 0.015 | 0.017 | 0.026 | 0.039 | 0.072 |
| Small Intestine | 0.020 | 0.026 | 0.044 | 0.071 | 0.013 |
| Heart | 0.013 | 0.016 | 0.026 | 0.039 | 0.072 |
| Kidneys | 0.027 | 0.033 | 0.046 | 0.069 | 0.12 |
| Liver | 0.017 | 0.022 | 0.032 | 0.048 | 0.088 |
| Lungs | 0.014 | 0.020 | 0.028 | 0.042 | 0.081 |
| Muscle | 0.012 | 0.014 | 0.023 | 0.036 | 0.067 |
| Esophagus | 0.012 | 0.015 | 0.023 | 0.036 | 0.069 |
| Ovaries | 0.015 | 0.018 | 0.028 | 0.043 | 0.077 |
| Pancreas | 0.014 | 0.018 | 0.027 | 0.043 | 0.078 |
| Skin | 0.009 | 0.011 | 0.18 | 0.029 | 0.055 |
| Spleen | 0.013 | 0.016 | 0.024 | 0.040 | 0.073 |
| Testes | 0.012 | 0.016 | 0.025 | 0.038 | 0.070 |
| Thymus | 0.012 | 0.015 | 0.023 | 0.036 | 0.069 |
| Thyroid | 0.012 | 0.015 | 0.024 | 0.039 | 0.073 |
| Uterus | 0.017 | 0.021 | 0.034 | 0.051 | 0.086 |
| Remaining organs | 0.012 | 0.014 | 0.022 | 0.035 | 0.066 |
| Effective dose [mSv/MBq | 0.016 | 0.021 | 0.031 | 0.047 | 0.082 |

## Distribution

[$^{18}$F]FET has a relatively short shelf life which is a result of radioactive isotope fluorine-18 half life (109.8 minutes). However, in comparison to radiotracers labelled with carbon-11 isotope, it still allows for radiotracer to be distributed through land and air up to 6 hour delivery radius.
Currently [$^{18}$F]FET is commercially available in Europe as IASOglio© in France (MA number 34009 550 105 1 7/34009 550 105 2 4) and in Poland (MA number 27420). The Marketing Authorization Holder is radiopharmaceutical company called Curium™.