**9. Acetate-based probes**

Acetate is transported into the cell via the monocarboxylic acid transporter where it is converted in mitochondria to acetyl-coenzyme A (acetyl-CoA) (Lopresti and Mason 2009). Acetyl-CoA is a substrate for several biochemical pathways, most notably the tricarboxylic acid (TCA) cycle, and for glutamine and lipid synthesis. Additional studies have demonstrated that the preferential use of acetate by astrocytes is mediated by transport, although the exact mechanism is not fully understood (Lopresti and Mason 2009). In a clinical study, Yamamoto et al. (2008) evaluated [11C]acetate for detecting brain gliomas and differentiating high-grade gliomas. Sensitivities of [11C]acetate, [11C]MET, and [18F]FDG were 90%, 100%, and 40%, respectively. The T/N ratios of [11C]acetate and [11C]MET were significantly higher than that of [18F]FDG. With respect to tumor grades, uptakes (SUVs) of [11C]acetate and [18F]FDG in high-grade gliomas were significantly higher than those in lowgrade gliomas while no significant differences were observed with [11C]MET. In another clinical study (Tsuchida et al. 2008), [11C]acetate was superior to [18F]FDG in differentiating high-grade tumors from low-grade tumors. In a recent preclinical animal study (Marik et al. 2009), the fluorinated form of acetate, [18F]fluoroacetate, was evaluated for the assessment of several neuropathologies including glioblastoma represented by the orthotopic U87 xenografts, ischemia associated with stroke or hypoxia. In this study, [18F]fluoroacetate showed the highest T/N ratio in glioblastoma followed by stroke-ischemia and hypoxiaischemia.

### **10. Conclusions**

PET imaging offers a growing "toolbox" of molecular imaging probes for noninvasive evaluation of gliomas. In general, [18F]FDG-PET has high prognostic value, performs well in identifying anaplastic transformations and detecting malignant high grade gliomas. But due to high normal cerebral uptake, it has limited use in detection of low-grade gliomas and residual/recurrent gliomas. Amino acid based probes (e.g, [11C]MET, [18F]FET and [18F]FDOPA) have low normal cerebral uptake, resulting in improved detection of lowgrade lesions. They have shown utility for grading of gliomas and they can differentiate residual/recurrent tumor from post-operative radiation injury. Preclinical studies with sigma receptor ligands suggest them to be more selective but less sensitive for tumor lesions than [18F]FDG, [11C]MET and [11C]choline. Use of somatostatin receptor ligands may be

showed a tumor-to-brain ratio of 1.9 and a tumor-to-blood ratio of 2.6 at 2 hours postinjection. In a recent clinical study by Shibahara et al. (2010), 8 patients with gliomas of different grades underwent PET studies with a new imidazole based hypoxia imaging agent, 1-(2-[18F]fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole ([18F]FRP-170). The new agent showed higher image contrast and faster clearance than [18F]FMISO. [18F]FRP-170 images showed positive correlation with HIF-1 expression, a weak correlation with [18F]FDG-PET and MR, but no correlation with [11C]MET-PET. The [18F]FRP-170-PET images showed marked uptake in the 3 GBM, and moderate uptake in recurrent anaplastic astrocytoma and oligodendroglioma, but no uptake in the other tumors (oligodendroglioma and diffuse astrocytoma). It is suggested that the use of hypoxia markers in patients with primary or recurrent gliomas could potentially assist in defining hypoxic tumor regions and

Acetate is transported into the cell via the monocarboxylic acid transporter where it is converted in mitochondria to acetyl-coenzyme A (acetyl-CoA) (Lopresti and Mason 2009). Acetyl-CoA is a substrate for several biochemical pathways, most notably the tricarboxylic acid (TCA) cycle, and for glutamine and lipid synthesis. Additional studies have demonstrated that the preferential use of acetate by astrocytes is mediated by transport, although the exact mechanism is not fully understood (Lopresti and Mason 2009). In a clinical study, Yamamoto et al. (2008) evaluated [11C]acetate for detecting brain gliomas and differentiating high-grade gliomas. Sensitivities of [11C]acetate, [11C]MET, and [18F]FDG were 90%, 100%, and 40%, respectively. The T/N ratios of [11C]acetate and [11C]MET were significantly higher than that of [18F]FDG. With respect to tumor grades, uptakes (SUVs) of [11C]acetate and [18F]FDG in high-grade gliomas were significantly higher than those in lowgrade gliomas while no significant differences were observed with [11C]MET. In another clinical study (Tsuchida et al. 2008), [11C]acetate was superior to [18F]FDG in differentiating high-grade tumors from low-grade tumors. In a recent preclinical animal study (Marik et al. 2009), the fluorinated form of acetate, [18F]fluoroacetate, was evaluated for the assessment of several neuropathologies including glioblastoma represented by the orthotopic U87 xenografts, ischemia associated with stroke or hypoxia. In this study, [18F]fluoroacetate showed the highest T/N ratio in glioblastoma followed by stroke-ischemia and hypoxia-

PET imaging offers a growing "toolbox" of molecular imaging probes for noninvasive evaluation of gliomas. In general, [18F]FDG-PET has high prognostic value, performs well in identifying anaplastic transformations and detecting malignant high grade gliomas. But due to high normal cerebral uptake, it has limited use in detection of low-grade gliomas and residual/recurrent gliomas. Amino acid based probes (e.g, [11C]MET, [18F]FET and [18F]FDOPA) have low normal cerebral uptake, resulting in improved detection of lowgrade lesions. They have shown utility for grading of gliomas and they can differentiate residual/recurrent tumor from post-operative radiation injury. Preclinical studies with sigma receptor ligands suggest them to be more selective but less sensitive for tumor lesions than [18F]FDG, [11C]MET and [11C]choline. Use of somatostatin receptor ligands may be

predicting response to radiotherapy, but is not effective for grading tumors.

**9. Acetate-based probes** 

ischemia.

**10. Conclusions** 

limited to detecting meningiomas, while hypoxia markers are best suited for disease prognosis and predicting response to radiotherapy. Recent studies with choline-, acetateand integrin-based PET probes seem encouraging but more work is needed to fully appreciate their potential. In conclusion, positron-labeled amino acids are showing highest general utility for staging and therapy management of gliomas, while other metabolic probes are undergoing validation to answer selected clinical questions such as assessment of hypoxia and angiogenesis.

#### **11. Acknowledgement**

The authors thank Drs. Sandi A. Kwee and Laura Horky for their contributions. The work was supported by the US Department of Energy (DE-FG02-10ER41691, (TRD)) and NIH (R21 EB0110085 (TRD)).

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**10** 

Rainer Ritz

*Germany* 

**Visualization and Photodynamic** 

**Therapy in Malignant Glioma -** 

**An Overview and Perspectives** 

*Department of Neurosurgery, Eberhard Karls University Tübingen, Tübingen* 

Photodynamic therapy (PDT) is a relatively new modality of cancer treatment. Actual ongoing clinical era started with the studies of Dougherty in the 1970s. PDT is based on the application of a so called photosensitizer (PS), which preferably enriches in the tumor tissue. The application of light at an appropriate wavelength excites the PS molecules from their ground state S0 to an electronically excited singlet state Sx. The energy of the excited state can be dissipated via several relaxation pathways. By this, so called cytotoxic reactive oxygen species (ROS) are generated. ROS react with various biomolecules inducing cell

The newer history of PDT starts with the observations of Von Tappeiner and Raab at the Maximilian Ludwig University in Munich. In 1900, Raab first reported on the chemical sensitisation of tissue by light.(Raab 1900) Von Tappeiner described in 1904 the so called "photodynamic reaction".(Tappeiner & Jodlbauer 1904) He believed that this effect was based on fluorescence. In contrast Neiser (Breslau) and Dreyer (Finsen Institue in Kopenhagen) described a sensitisation by light for photodynamic reaction.(Dreyer 1903;Neisser & Halberstaedtter 1904) At this time Ledoux-Lebards already proved the concept of the presence of oxygen as a condition for PDT at the Institute Pasteur in Paris (1902).(Ledoux-Lebards 1902) In this era skin diseases were treated with chinidin, acridin

Already from the beginning of PDT, haematoporphyrin (Hp) was of special interest. Hausmann used Hp for photodynamic investigations in mice in 1911.(Hausmann 1911) In 1913, Meyer-Betz studied Hp to determine its biological effects on himself. After exposition to sunlight he suffered from extensive phototoxic reactions.(Meyer-Betz 1913) Policard detected 1924 in rat sarcoma a red fluorescence after Hp administration.(Policard 1924) In 1942 Auler and Banzer reported on the affinity of neoplastic tissues for Hp in tumor, metastases and lymphatic vessels in patients suffering cancer.(Auler & Banzer 1942) Further investigations were performed by Figge et al. in 1948; they demonstrated the properties of Hp to localize tumors.(Figge, Weiland, & Manganiello 1948) Due to high toxic reactions of

death by different mechanims.(Dougherty et al. 1998b)

**1. Introduction** 

**2. History of PDT** 

and eosin with unsatisfying results.

FDG for differentiating tumor from inflammation in a rodent model, *J Nucl Med*, Vol.45, No.4, pp. 695-700, ISSN 0161-5505

