**3.3 [18F]FDOPA**

In mammalian cells, L-DOPA is synthesized from the amino acid, L-tyrosine, by the enzyme tyrosine hydroxylase (Kaufman 1995). L-DOPA is a precursor of the neurotransmitters: dopamine, norepinephrine, and epinephrine (Nagatsu 1995). L-DOPA is taken up by the brain through the blood-brain barrier (BBB) mediated by large neutral amino acid transporters (Lemmens et al. 2005). The [18F]fluorinated L-DOPA analog, [18F]FDOPA was initially developed as a radiotracer for use in patients with movement disorders (Heiss et al. 1996). In an early study, [18F]FDOPA-PET of a 57 y old patient revealed pathologically increased [18F]FDOPA accumulation in the right frontal lobe (Heiss et al. 1996). Unexpectedly, further PET examinations demonstrated increased [11C]MET uptake and low [18F]FDG uptake in this

PET Imaging of Gliomas 167

Potential use of [18F]FDOPA in tumor grading was also supported by a recent study by Chen et al. (2006) that showed significantly higher uptake in high-grade than in low-grade tumors in newly diagnosed tumors. This correlation was not seen in recurrent tumors that had been treated previously. In summary, [18F]FDOPA-PET has been found useful in detecting and differentiating recurrent tumors from radiation necrosis and may also have potential in grading newly diagnosed tumors, although more studies are needed to fully

A number of other positron-labeled amino acid analogs have been developed for imaging of brain tumors, although having fewer clinical trials to determine their characteristics for imaging of gliomas. These include [124I]iodophenylalanine (Farmakis et al. 2008), [18F]fluoromethylphenylalanine (FMP), [18F]fluoroboronophenylalanine (FBP) (Hsieh et al. 2005; Imahori et al. 1998), [18F]fluoroethylphenylalanine (FEP) (Wang et al. 2011) and [18F]fluoropropylphenylalanine (FPP) (Wang et al. 2011), and 1-Aminocyclobutane-1-

In recent years, choline metabolism has received a growing interest in cancer research. Choline is incorporated into membrane phospholipid in the form of phosphatidylcholine through the multistep Kennedy pathway. Phosphatidylcholine is one of the major lipid components of plasma membranes in mammalian cells and is essential for membrane structural stability and cell proliferation. Following its transport into the cell, choline undergoes ATP-dependent phosphorylation to form phosphocholine, a reaction catalyzed by choline kinase. High levels of choline uptake and increased choline kinase activity relative to normal tissues have been reported in various cancers including brain tumors (Fulham et al. 1992). This has motivated the development of choline based PET imaging for

Shinoura et al. (1997) were the first to use choline as a PET tracer of brain tumor imaging. They evaluated 20 patients with brain tumors using [11C]choline PET. Progressive uptake of [11C]choline was observed in brain tumors, while uptake by surrounding normal cerebral cortex was 10-fold lower. Later, Ohtani et al. (2001) compared [11C]choline-PET with [18F]FDG-PET in 22 patients with histopathologically confirmed benign lesions and brain tumors from grade I-IV. Higher uptake of [11C]choline relative to [18F]FDG was observed in high-grade grade III and grade IV gliomas. Furthermore, [11C]choline was able to detect the extent of tumor better than MRI and could differentiate high-grade from low-grade lesions,

The short half-life of [11C]choline limits the use of this tracer to facilities having an on-site cyclotron. In view of this, a choline radiotracer with a longer half-life is highly desirable. [18F]Fluorinated analogs of choline [18F]FCH are promising options for choline based PET

DeGrado et al. (2001) first reported brain tumor imaging with [18F]FCH in a patient with previously resected anaplastic astrocytoma. The maximal T/N ratio of 10:1 was attained within 5 min after injection. [18F]FDG -PET revealed a corresponding area of increased [18F]FDG uptake; however, the tumor boundaries were difficult to assess with FDG because of high uptake by normal cortex. Hara et al. (2003) performed studies with [18F]fluoroethylcholine (FECH) in 12 glioma patients. The T/N ratio of [18F]FECH was 10.5- 12 in anaplastic astrocytoma and 13.2-21 in glioblastoma. These ratios were slightly higher

define the potential of [18F]FDOPA-PET.

**4. Choline-based probes** 

noninvasive evaluation of gliomas.

tumor imaging.

[11C]carboxylic acid (1-[11C]-ACBC) (Hubner et al. 1998).

but could not differentiate low-grade lesions from benign lesions.

right frontal region, suggesting a low-grade glioma lesion. MRI, 1H-MRSI and histological examination later confirmed presence of a grade II oligo-astrocytoma in the lesion.

Following this incidental discovery, various studies were performed to evaluate the potential of [18F]FDOPA-PET for imaging of gliomas. Chen et al. (2006) compared [18F]FDOPA-PET with [18F]FDG-PET to evaluate the potential of [18F]FDOPA-PET to detect tumor lesions in patients with newly diagnosed or previously treated brain tumors. The [18F]FDOPA-PET images were acquired for 10–30 min post-injection. In this study, [18F]FDOPA-PET demonstrated excellent visualization of both low-grade and high-grade tumors, although the absolute uptake was not significantly different between the different tumor grades. [18F]FDOPA-PET was more sensitive and specific than [18F]FDG-PET for evaluating and distinguishing recurrent tumors from radiation necrosis. Specific transport of [18F]FDOPA (Lemmens et al. 2005) independent of disruption of BBB and low background activity rendered it superior to MRI and [18F]FDG for detecting recurrent gliomas.

A number of subsequent studies have suggested that tumor grade does not significantly affect [18F]FDOPA uptake (**Figure 4**) (Chen et al. 2006; Duan et al. 2004; Jager et al. 2001; Li and Zhang 2004; Ono et al. 2004). However, Schiepers et al. (2007) used kinetic modeling of [18F]FDOPA time courses out to 75 min to show that high-grade tumors had significantly higher transport rate constant, k1, equilibrium distribution volumes, and influx rate constant K than did low-grade tumors (P< 0.01). A 3-compartment model with corrections for tissue blood volume, metabolites, and partial volume, suggested that [18F]FDOPA was transported but not trapped in tumors. The shape of the uptake curve appeared to be related to tumor grade. After an early maximum, high-grade tumors had a steep descending branch, whereas low-grade tumors had a slowly declining curve, like that for the cerebellum but on a higher scale. A high correlation was found between SUV in tumors and influx rate constant K, indicated that simple uptake measurements at 60-70 min should be sufficient in clinical practice for grading tumors.

Fig. 4. Patient with newly diagnosed (A) GBM (B) Grade II oligodendroglioma. Tumor lesion shown as region with contrast enhancement in T1-weighted MRI (left). This region is not visible in [18F]FDG-PET scan (middle) but a prominent [18F]FDOPA uptake is seen in this region in [18F]FDOPA-PET scan (right). *Image adapted from work by Wei Chen et al. (2006) and used with permission.*

right frontal region, suggesting a low-grade glioma lesion. MRI, 1H-MRSI and histological

Following this incidental discovery, various studies were performed to evaluate the potential of [18F]FDOPA-PET for imaging of gliomas. Chen et al. (2006) compared [18F]FDOPA-PET with [18F]FDG-PET to evaluate the potential of [18F]FDOPA-PET to detect tumor lesions in patients with newly diagnosed or previously treated brain tumors. The [18F]FDOPA-PET images were acquired for 10–30 min post-injection. In this study, [18F]FDOPA-PET demonstrated excellent visualization of both low-grade and high-grade tumors, although the absolute uptake was not significantly different between the different tumor grades. [18F]FDOPA-PET was more sensitive and specific than [18F]FDG-PET for evaluating and distinguishing recurrent tumors from radiation necrosis. Specific transport of [18F]FDOPA (Lemmens et al. 2005) independent of disruption of BBB and low background activity rendered it superior to MRI and [18F]FDG

A number of subsequent studies have suggested that tumor grade does not significantly affect [18F]FDOPA uptake (**Figure 4**) (Chen et al. 2006; Duan et al. 2004; Jager et al. 2001; Li and Zhang 2004; Ono et al. 2004). However, Schiepers et al. (2007) used kinetic modeling of [18F]FDOPA time courses out to 75 min to show that high-grade tumors had significantly higher transport rate constant, k1, equilibrium distribution volumes, and influx rate constant K than did low-grade tumors (P< 0.01). A 3-compartment model with corrections for tissue blood volume, metabolites, and partial volume, suggested that [18F]FDOPA was transported but not trapped in tumors. The shape of the uptake curve appeared to be related to tumor grade. After an early maximum, high-grade tumors had a steep descending branch, whereas low-grade tumors had a slowly declining curve, like that for the cerebellum but on a higher scale. A high correlation was found between SUV in tumors and influx rate constant K, indicated that simple uptake measurements at 60-70 min should be sufficient in

Fig. 4. Patient with newly diagnosed (A) GBM (B) Grade II oligodendroglioma. Tumor lesion shown as region with contrast enhancement in T1-weighted MRI (left). This region is not visible in [18F]FDG-PET scan (middle) but a prominent [18F]FDOPA uptake is seen in this region in [18F]FDOPA-PET scan (right). *Image adapted from work by Wei Chen et al. (2006) and* 

examination later confirmed presence of a grade II oligo-astrocytoma in the lesion.

for detecting recurrent gliomas.

clinical practice for grading tumors.

*used with permission.*

Potential use of [18F]FDOPA in tumor grading was also supported by a recent study by Chen et al. (2006) that showed significantly higher uptake in high-grade than in low-grade tumors in newly diagnosed tumors. This correlation was not seen in recurrent tumors that had been treated previously. In summary, [18F]FDOPA-PET has been found useful in detecting and differentiating recurrent tumors from radiation necrosis and may also have potential in grading newly diagnosed tumors, although more studies are needed to fully define the potential of [18F]FDOPA-PET.

A number of other positron-labeled amino acid analogs have been developed for imaging of brain tumors, although having fewer clinical trials to determine their characteristics for imaging of gliomas. These include [124I]iodophenylalanine (Farmakis et al. 2008), [18F]fluoromethylphenylalanine (FMP), [18F]fluoroboronophenylalanine (FBP) (Hsieh et al. 2005; Imahori et al. 1998), [18F]fluoroethylphenylalanine (FEP) (Wang et al. 2011) and [18F]fluoropropylphenylalanine (FPP) (Wang et al. 2011), and 1-Aminocyclobutane-1- [11C]carboxylic acid (1-[11C]-ACBC) (Hubner et al. 1998).
