CS 
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Fluorine-18-labelled misonidazole, 2-nitro-3-(1-18fluoro-2-hydroxypropan-3-yl)imidazole, better known by the abbreviation [18F]FMISO, is currently the most widely used radioactive tracer for studying tumour hypoxia by positron emission tomography (PET). Hypoxia is defined as a reduced intracellular oxygen pressure, caused either by a reduced supply of, or an increased demand for, oxygen. The partial pressure of oxygen in normally oxygenated tissue commonly exceeds 40 mm Hg.
Hypoxia has been demonstrated in many disease states before, using various invasive methods such as immunohistochemistry. It is clear that hypoxia is present in conditions such as stroke or ischaemia of the heart muscle, but tumour hypoxia in particular is an important indicator of prognosis and of the body's response to treatment. The distribution of [18F]FMISO in the body takes place independently of blood flow, which also satisfies one of the main requirements for this type of tracer. [18F]FMISO-PET thus offers a suitable and currently very widespread way of non-invasively determining tissue hypoxia.
Properties
[18F]FMISO contains the fluorine radionuclide 18F. Fluorine 18F decays by positron emission (β+) with a half-life of 109.7 minutes. For diagnostic imaging by positron emission tomography (PET), the most important are the emitted γ photons with an energy of 511 keV, formed by the interaction of the emitted positrons with electrons (so-called positron annihilation). PET diagnostics using [18F]FMISO is a very advantageous method for locating hypoxic tissue in almost the entire human body. Its main application is found particularly in tumours of the brain, head and neck. The degree of hypoxia correlates significantly with the aggressiveness of tumours and their resistance to subsequent chemotherapy and radiotherapy.
Pharmacokinetics
Pharmacodynamics
[18F]FMISO passes through the cell membrane, including the blood–brain barrier, by passive diffusion into the cytoplasm, where it is immediately reduced by intracellular nitroreductases. In cells with a reduced partial pressure of oxygen, covalent binding to cellular molecules occurs at a rate that is inversely proportional to the intracellular oxygen concentration. The resulting nitro radical accepts a further electron to form an intermediate (R-NO). The intermediate is then further reduced to a strong alkylating agent (R-NH2), which subsequently reacts with macromolecules such as DNA, RNA and proteins. In cells with sufficient oxygen, the product is rapidly re-oxidised and the metabolites do not accumulate in the cell. Because accumulation of [18F]FMISO occurs only in cells with active nitroreductases, it is retained only in living hypoxic cells, but not in necrotic cells.
Pharmacokinetics
Fluoromisonidazole is a small molecule with a molecular weight of around 190 Da. The partition coefficient in the octanol/water system for [18F]FMISO is around 0.41. This corresponds to its lipophilicity and also to its ability to diffuse freely and distribute homogeneously throughout the body as early as 1 hour after administration, independently of blood flow. The distribution kinetics of 2-nitroimidazoles generally correspond to a linear two-compartment open model.
Quantification of the presence of [18F]FMISO by the tumour/plasma ratio is optimally performed 2 hours after administration, when the values of [18F]FMISO in normal tissue are already balanced with those in plasma and hypoxic tissues continue to selectively retain [18F]FMISO.
The usual route of elimination of [18F]FMISO is renal. A small fraction of [18F]FMISO is glucuronidated, which increases its water solubility, and it is then easily excreted by the kidneys into the urine as a conjugate. A small amount (<5%) is converted to aminoimidazole.
Toxicity
At present, the usual total administered dose of [18F]FMISO in a radiodiagnostic examination is less than 15 μg. Given the very small total dose administered and also the mechanism of action of [18F]FMISO, toxicity and pharmacokinetic interactions with other medicinal products appear very unlikely. On the basis of many studies performed, it can be stated that at the doses administered for radiodiagnostic purposes, the preparation has no toxic effects.
The only risk, as with all diagnostic radiopharmaceuticals, is the amount of administered radioactivity. Fluorine-18 is a high-energy emitter (511 keV); on the other hand, its very short physical half-life (110 minutes) significantly reduces the duration of the radiation burden on the target tissues. When 3.7 MBq/kg is administered, the whole-body dose for a man (70 kg) is 0.013 mGy/MBq and for a woman (57 kg) 0.016 mGy/MBq. The effective dose equivalent is 0.0134 mSv/MBq for a man (70 kg) and 0.0140 mSv/MBq for a woman (57 kg).
It can be summarised that the organ doses for [18F]FMISO are comparable with other commonly used nuclear medicine examinations, and the potential radiation risk associated with [18F]FMISO PET studies is within generally accepted limits.
Use
[18F]FMISO is a robust radiopharmaceutical used to obtain images for determining the extent of hypoxia using PET imaging. Imaging of hypoxia in various types of tumour growth has already been the subject of a whole series of scientific publications. For clinical applications, [18F]FMISO has been used for over 10 years in a number of countries in Europe, the USA and Australia, and it is currently the most widely used preparation for determining the degree of hypoxia in both oncological and non-oncological indications.
Oncological applications
The main use of [18F]FMISO is in administration to oncology patients. It has been shown that the presence of hypoxia is significantly associated with resistance to chemotherapy and radiotherapy and accelerates tumour progression. There is growing evidence that hypoxia-mediated aggressive tumour behaviour and resistance to therapy is brought about via the heterodimeric transcription factor HIF-1 (hypoxia inducible factor-1) through molecular processes that allow tumour cells to adapt to hypoxia, such as unregulated glycolysis, angiogenesis and p53 mutations. HIF-1 activates the transcription of genes whose protein products play a role either in increasing oxygen availability or in enabling metabolic adaptation to a hypoxic environment. The HIF-1 protein is overexpressed in a wide range of tumours and in their metastases. Benign non-invasive tumours mostly do not express HIF-1 at all. Strong expression of HIF-1 has been observed in glioblastomas and haemangioblastomas, which are among the most malignant and highly vascularised tumours of the nervous system. There is also a significant correlation between HIF-1 expression and apoptotic and pro-apoptotic factors.
Both in vitro and in vivo studies show that hypoxia can significantly alter cell behaviour, e.g. by expansion of cells with a low apoptotic index and an increasing rate of cell mutations. Hypoxia causes an increase in the expression of genes related to tumour cell survival (e.g. VEGF (vascular endothelial growth factor), glycolytic enzymes, signalling molecules) and also cell adaptation to a hypoxic environment (inhibition of apoptosis and cell differentiation, increased angiogenesis). These adaptive changes in the genome and proteome of tumour cells result in a much more aggressive phenotype of these cells.
It has been shown that, compared with normal cells, hypoxic cells are several times more resistant to ionising radiation, which subsequently leads to resistance to radiotherapy. In hypoxic tissue, it is necessary to irradiate with a dose 2.5 to 3.5 times higher than in normoxic tissue for the same radiotherapeutic effect. Knowledge of the degree of hypoxia in a tumour helps in choosing the right strategy in the treatment of a tumour disease.
It is precisely the growing need to detect the degree of hypoxia as a prognostic marker that has led to efforts to determine the extent of hypoxia as objectively as possible. The gold standard for determining the amount of oxygen used to be the invasive method using an oxygen electrode. At present, the most widespread and most studied non-invasive method of determining hypoxia is precisely the combination of the [18F]FMISO radiotracer with PET imaging.
Although [18F]FMISO can generally be used to determine hypoxia in a whole range of tumours, its most common use is in tumours of the central nervous system (meningiomas and highly malignant gliomas) and malignant tumours of the head and neck.
Non-oncological applications
The use of [18F]FMISO for non-oncological determination of hypoxia is primarily focused on brain hypoxia, and subsequently on myocardial hypoxia. The most commonly studied cases are monitoring the extent of hypoxia in ischaemia of brain tissue and acute stroke, as well as myocardial ischaemia and the extent of tissue damage after myocardial infarction. There are also studies dealing with the detection of anaerobic infection of the body using [18F]FMISO.
Conclusion
Determining the degree of hypoxia using [18F]FMISO-PET is an easy procedure that is very well tolerated by patients. The imaging itself takes 20–30 min and begins 75–150 min after administration of the radiopharmaceutical. Well-contrasted images can be obtained using a medium radiation dose, commonly around 250 MBq, similar to a skeletal examination.
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