**3.1 [11C]MET**

Increased uptake of methionine by cancer cells results from increased transport flux, primarily by L-amino acid transporters, enhanced protein synthesis, increased need for polyamines, and a high rate of trans-methylation and trans-sulfuration reactions (Leskinen-Kallio et al. 1991). [11C]MET uptake in tumor lesions is not dependent on disruption of the BBB (Roelcke et al. 1995; Sasajima et al. 2004). This is a major advantage compared to MRI where contrast enhancement for detection of tumor lesions is dependent on BBB disruption. Studies with [11C]MET-PET have shown that amino acid tracer, [11C]MET, accumulates in all gliomas, including low-grade glioma that are difficult to detect on contrast-enhanced MRI and [18F]FDG-PET (Ogawa et al. 1993).

[11C]MET-PET can be used to predict histological grades of gliomas. Lilja et al. (1985) evaluated 14 patients with gliomas and found that [11C]MET-PET could differentiate highgrade glioma from low-grade glioma on the basis of T/N ratio. The ratio of the uptake of [11C]MET in high-grade tumors was 1.9-4.8 and low-grade tumor was 0.8-1.0. Derlon et al. (1989) too confirmed positive correlation of T/N ratio with the histological grade of gliomas. Later study with large set of 196 patients, Herholz et al. (1998) showed that [11C]MET could differentiate among high-grade gliomas, low-grade gliomas, and chronic or subacute nontumoral lesions. In this study, [11C]MET-PET was also useful in detecting recurrent or residual tumors as they showed higher [11C]MET uptake than primary gliomas.

[11C]MET-PET has been shown to have high prognostic potential. Kaschten et al. (1998) performed [18F]FDG-PET and [11C]MET-PET in 54 patients with gliomas. [11C]MET was superior to [18F]FDG in predicting the histologic grade and prognosis of gliomas. With a larger set of 85 patients, De Witte et al. (2001) applied qualitative and quantitative scoring systems for [11C]MET uptake. Both scoring systems confirmed the prognostic importance of [11C]MET-PET. In this study, gliomas were histologically graded following [11C]MET-PET guided resection (42 cases) or stereotactic biopsy (43 cases). Uptake of [11C]MET was present in 98% of the gliomas studied. The T/N ratio was significantly correlated with the histological grade of glioma. A statistically poor patient outcome was demonstrated during follow-up when this ratio was higher than a threshold of 2.2 for grade II gliomas and 2.8 for grade III gliomas. A high [11C]MET uptake was statistically associated with short survival times. Better prognostic utility of [11C]MET-PET relative to [18F]FDG-PET was also shown in other studies (Kim et al. 2005; Van Laere et al. 2005).

[11C]MET-PET is also useful to differentiate recurrent tumor from post-operative radiation injury (Gehrke et al. 1991; Ogawa et al. 1991; Sonoda et al. 1998). Tsuyuguchi et al. (2003) examined 21 adult patients with [11C]MET-PET to differentiate radiation necrosis from recurrent metastatic brain tumor following stereotactic radiosurgery. They observed mean

PET Imaging of Gliomas 165

studied 53 patients with low grade (1 grade I, 9 grade II) or high grade gliomas (16 grade III, 27 grade IV) and clinically suspected recurrent tumors. The patients underwent [18F]FET-PET scans 4-180 months after various treatments. In the 42 patients with confirmed recurrence, there was additional distinct focal [18F]FET uptake with significantly higher

Fig. 3. Patient with residual tumor after subtotal resection of GBM (top) and a patient with radiation induced changes after radiotherapy for metastatic melanoma (bottom). T1-

weighted contrast-enhanced MRI showing contrast enhancement in both residual tumor (A, top) and radiation induced injury (A, bottom). In the patient with residual GBM, [11C]MET-PET (B, top) and [18F]FET-PET (C, top) shows markedly increased tracer uptake. However, there is no increased uptake of [11C]MET (B, bottom) and [18F]FET (C, bottom) in radiation induced injury. *Image reproduced from work by Wolfgang A. Weber et al. (2000) and used with* 

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

*permission.* 

**3.3 [18F]FDOPA** 

values compared with those in the 11 patients without clinical signs of recurrence.

T/N ratio and mean SUV for [11C]MET to be 1.15 and 1.78, respectively, in the radiation necrosis group (12 cases); and 1.62 and 2.5, respectively, in the tumor recurrence group (9 cases). The sensitivity and specificity of [11C]MET-PET for detection of tumor recurrence were determined to be 77.8% and 100%, respectively. In a separate study, [11C]MET-PET was shown to be superior to [18F]FDG-PET in detecting recurrent brain lesions (Chung et al. 2002). A recent study by Okamoto et al. (2010) further confirmed the utility of [11C]MET-PET to detect recurring lesions. Mean T/N ratio of all recurrent tumors and necrosis were 1.98 ± 0.62 and 1.27 ± 0.28, respectively (p < 0.01) (Okamoto et al. 2010). In smaller lesions (20 – 30 mm), T/N ratio for recurrent tumor (1.72 ± 0.44) was also significantly higher than that for necrosis (1.20 ± 0.11) (p < 0.01) (Okamoto et al. 2010). Thus, [11C]MET-PET provides high diagnostic value for recurring tumor lesions, with particular value in early diagnosis of recurrence.
