**7. Hypoxia radiotracers**

Hypoxia is an important factor in the malignant progression of tumour and its resistance to therapy. The majority of hypoxia PET radiotracers belong to a group of compounds known as nitroimidazoles that freely cross the blood–brain barrier, enter cells by diffusion and are subsequently reduced by nitroreductases at a rate inversely proportional to oxygen tension. Thus, in an oxygen-rich environment, they are able to diffuse back out ofthe cell again, whereas under hypoxic conditions, they are reduced and become irreversibly trapped in the cell. Anotherfavourable property ofthe nitroimidazoles is theirrapid equilibration within the brain parenchyma independently of perfusion.

#### **7.1. Fluoromisonidazole**

F-18 fluoromisonidazole (FMISO) was the first of the nitroimidazole radiotracers (**Figure 10**) to be developed for imaging with PET and has been widely used in preclinical and clinical studies.

**Figure 10.** Nitroimidazoles are the most commonly used hypoxia PET radiotracers. FMISO: fluoromisonidazole; FA‐ ZA: fluoroazomycin; FETNIM: fluoroerythronitroimidazole.

Hypoxia can be quantified by analysing FMISO PET images using a simple tissue-to-blood ratio of radiotracer activity, with a ratio of 1.2 or greater useful for discriminating and quantifying hypoxic tissue. Hypoxic tumour volume and maximal tumour-to-blood ratio calculated in this way has been shown to predict worse prognosis independent of other factors [51]. FMISO can also differentiate lower from higher grade gliomas better than FDG [52].

More recently, an image-derived region to assess blood activity on FMISO PET has been shown to be an accurate surrogate for serial blood sampling in the quantification of hypoxia [53] and this may obviate the need for routine venous sampling in patients undergoing FMISO PET in the future.
