**4. Amino acid radiotracers**

Amino acids are the building blocks of proteins and critical to nearly every biological process in the human body. They serve as components in metabolic cycles which are upregulated in cancer cells with increased proliferative activity. Because the brain uses glucose almost

exclusively for fuel (except during prolonged starvation), PET imaging of brain tumours with amino acid and amino acid analogue radiotracers has a significant advantage of high tu‐ mour-to-background contrast (**Figure 3**).

**Figure 3.** F-18 FDG PET/CT (*top row*) and F-18 FDOPA PET/CT (*bottom row*) of a left frontotemporal low-grade nonenhancing cerebral glioma showing the high tumour-to-background contrast of amino acid imaging compared with metabolic imaging.

#### **4.1. Methionine**

Methionine (MET) is a sulphur-containing naturally occurring amino acid (**Figure 4**) whose transport into malignant glioma cells and the supporting vasculature of these tumours is strongly upregulated [20–22].

**Figure 4.** Chemical structure of methionine.

C-11 MET is one of the most widely used amino acid radiotracers for PET imaging in neuro‐ oncology, mainly due to its relative ease of production that can be performed rapidly with high yield and without the need for complicated purification steps.

The overall sensitivity of MET PET for malignant gliomas ranges from 76 to 95%, with higher rates of detection for higher grade tumours [23]. Increased uptake of MET is also seen in lowgrade gliomas—with reported sensitivities of 65–85% [23, 24]—in which there is typically little or absent contrast enhancement on MRI and low uptake on FDG PET [24, 25].

MET is also generally regarded as the reference in prognostication of disease, image-guided biopsy and radiotherapy planning, and the detection of tumour recurrence [26–34], making it the most important radiotracer in the amino acid category.

The main limitation of C-11 MET is its short half-life (20 min), confining its use to centres with a cyclotron on-site or very nearby. It has also been shown to accumulate in brain abscesses and inflammation (cerebritis) [35], important false positives to exclude in the diagnosis of brain tumour.

F-18 has a much longer half-life (110 min) than C-11 and opens up the possibility of radiotrac‐ er transport to another centre for diagnostic imaging. F-18 labelled amino acids include F-18 labelled fluoroethyltyrosine (FET) and dihydroxyfluorophenylalanine (FDOPA).

#### **4.2. Fluoroethyltyrosine**

exclusively for fuel (except during prolonged starvation), PET imaging of brain tumours with amino acid and amino acid analogue radiotracers has a significant advantage of high tu‐

**Figure 3.** F-18 FDG PET/CT (*top row*) and F-18 FDOPA PET/CT (*bottom row*) of a left frontotemporal low-grade nonenhancing cerebral glioma showing the high tumour-to-background contrast of amino acid imaging compared with

Methionine (MET) is a sulphur-containing naturally occurring amino acid (**Figure 4**) whose transport into malignant glioma cells and the supporting vasculature of these tumours is

C-11 MET is one of the most widely used amino acid radiotracers for PET imaging in neuro‐ oncology, mainly due to its relative ease of production that can be performed rapidly with

The overall sensitivity of MET PET for malignant gliomas ranges from 76 to 95%, with higher rates of detection for higher grade tumours [23]. Increased uptake of MET is also seen in low-

high yield and without the need for complicated purification steps.

mour-to-background contrast (**Figure 3**).

188 Neurooncology - Newer Developments

metabolic imaging.

**4.1. Methionine**

strongly upregulated [20–22].

**Figure 4.** Chemical structure of methionine.

FET is an artificial amino acid (**Figure 5**) taken up by upregulated tumour cells but not incorporated into proteins (unlike naturally occurring amino acids such as methionine). As such, its use in the characterisation of brain lesions and the grading of gliomas requires dynamic analysis of activity over time [36]. Its overall accuracy in the diagnosis of gliomas is comparable to MET [37, 38]. It is an excellent tool for differentiating tumour from non-tumour causes in the initial evaluation of newly diagnosed brain lesions [39] (**Figure 6**). FET PET can also distinguish active tumour from radiation necrosis following treatment [40, 41].

**Figure 5.** Chemical structure of F-18 fluoroethyltyrosine.

**Figure 6.** FET PET/CT (*left-sided panels*) and pre/post intravenous gadolinium MRI (*right-sided panels*) in a patient with two small cerebral melanoma metastases (*red and blue arrows*).

#### **4.3. Fluorodihydroxyphenylalanine**

FDOPA was originally developed for imaging the DOPA-decarboxylase pathway in Parkinson's disease and other neurodegenerative diseases. It is a fluorinated form of L-DOPA (**Figure 7**) which is used to increased dopamine concentrations in the treatment of Parkinson's disease. FDOPA has since been shown to be a marker of amino acid transport in brain tumours and metastases.

**Figure 7.** Chemical structure of F-18 fluorodihydroxyphenylalanine.

FDOPA uptake has been shown to correlate with tumour proliferation and grade [42], and more accurate than FDG for evaluating low-grade tumours and distinguishing tumour recurrence from radiation necrosis [43].

It also accumulates in neuroendocrine tumours (NETs) such as phaeochromocytomas and paragangliomas.

## **5. Fluorothymidine**

Thymidine (T) is the pyrimidine deoxynucleoside in DNA that pairs with deoxyadenosine (A). F-18 fluorothymidine (FLT) is a thymidine analogue (**Figure 8**) and a substrate for thymi‐ dine kinase 1 (responsible for synchronising cells in G1/early S phase), but unlike thymidine, FLT is a poor substrate for mitochondrial thymidine kinase 2 and its uptake is therefore specific to the cell cycle and a marker of cellular proliferation.

**Figure 8.** Chemical structure of F-18 fluorothymidine.

FLT uptake in normal brain cells is limited by the blood–brain barrier, thus FLT PET pro‐ vides higher tumour-to-background contrast than FDG PET. FLT is more sensitive than FDG PET for the detection of recurrent high-grade glioma and also correlates better with tumour progression and survival [44].

However, its use as a quantitative marker of the activity of DNA synthesis in gliomas remains a subject of debate, particularly whether FLT can discriminate moderately proliferative tumours driven by thymidine salvage pathway utilisation from highly proliferative tumours primarily driven by de novo synthesis of thymidine. Quantitative FLT PET with kinetic modelling may also beusefulfordistinguishing glioma recurrence from radiation necrosis [45].
