18f-faza and fluoromisonidazole

18F-FDG is a most popular radiopharmaceutical for tumor diagnosis in the world. In addition, 11C-methionine, 18F-FLT and 11C-choline have been used to compensate for drawbacks of 18F-FDG. Now, novel radiopharmaceuticals are required to estimate or predict therapeutic efficacy because we have many strategies to treat tumors. Radiotherapy which damage DNA by producing free radicals is commonly used to treat various types of tumors. Hypoxia is closely associated with resistance to chemo- and/or radiotherapy and is a common feature of solid tumors. Recently, understanding of tumor hypoxia in oncology has led to development of radiopharmaceuticals for hypoxia imaging. This review provides an overview of PET radiopharmaceuticals for hypoxia imaging and 18F-FBPA which is used for boron neutron capture therapy.

Topics: Animals; Boron Compounds; Boron Neutron Capture Therapy; Coordination Complexes; Fluorine Radioisotopes; Humans; Hypoxia; Misonidazole; Neoplasms; Nitroimidazoles; Organometallic Compounds; Phenylalanine; Positron-Emission Tomography; Radiopharmaceuticals; Thiosemicarbazones

Radiotherapy based on functional imaging consists to deliver a heterogeneity dose based on biological proprieties. This approach is termed biologically conformal radiotherapy or dose painting with biological target volume inside the gross tumor volume. Diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced MRI can also be used to define a specific biological target volume. Three main tracers are used: ((18)F)-fluorodeoxyglucose to target the hypermetabolism, ((18)F)-fluoromizonidazole and ((18)F)- fluoroazomycin arabinoside to target areas of hypoxia. In this review, we give a practical approach to achieving a treatment-guided radiotherapy molecular and the main issues raised by this imaging technique. Despite the provision of all the technological tools to the radiotherapist, this new therapeutic approach is still evaluated in clinical studies to demonstrate a real clinical benefit compared to radiotherapy based on anatomic imaging.

Topics: Carcinoma, Squamous Cell; Cell Hypoxia; Clinical Trials as Topic; Diffusion Magnetic Resonance Imaging; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Humans; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Misonidazole; Multimodal Imaging; Nitroimidazoles; Positron-Emission Tomography; Radiopharmaceuticals; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Image-Guided; Tumor Burden

Positron emission tomography (PET) has become a standard in staging Head and Neck cancer. While (18)F-fluoro-2-deoxy-D-glucose (FDG) is the most frequently used radiopharmaceutical, glycolysis is not the only metabolic process that can be visualized. Different PET tracers can also be used to visualize other metabolic processes and in this manner, the disadvantages of FDG PET can be avoided. In this review, we describe a comprehensive overview of alternatives to FDG that can be used in identifying head and neck cancer. The potential advantages and disadvantages of these radiopharmaceuticals are discussed.

Topics: Amino Acids; Antibodies, Monoclonal; Carbon Radioisotopes; Carcinoma, Squamous Cell; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Humans; Misonidazole; Nitroimidazoles; Nucleosides; Positron-Emission Tomography; Radiopharmaceuticals

Several individual clinical and preclinical studies have shown the possibility of evaluating tumor hypoxia by using noninvasive positron emission tomography (PET). The current study compared 3 hypoxia PET tracers frequently used in the clinic, [(18)F]FMISO, [(18)F]FAZA, and [(18)F]HX4, in a preclinical tumor model. Tracer uptake was evaluated for the optimal time point for imaging, tumor-to-blood ratios (TBR), spatial reproducibility, and sensitivity to oxygen modification.. PET/computed tomography (CT) images of rhabdomyosarcoma R1-bearing WAG/Rij rats were acquired at multiple time points post injection (p.i.) with one of the hypoxia tracers. TBR values were calculated, and reproducibility was investigated by voxel-to-voxel analysis, represented as correlation coefficients (R) or Dice similarity coefficient of the high-uptake volume. Tumor oxygen modifications were induced by exposure to either carbogen/nicotinamide treatment or 7% oxygen breathing.. TBR was stabilized and maximal at 2 hours p.i. for [(18)F]FAZA (4.0 ± 0.5) and at 3 hours p.i. for [(18)F]HX4 (7.2 ± 0.7), whereas [(18)F]FMISO showed a constant increasing TBR (9.0 ± 0.8 at 6 hours p.i.). High spatial reproducibility was observed by voxel-to-voxel comparisons and Dice similarity coefficient calculations on the 30% highest uptake volume for both [(18)F]FMISO (R = 0.86; Dice coefficient = 0.76) and [(18)F]HX4 (R = 0.76; Dice coefficient = 0.70), whereas [(18)F]FAZA was less reproducible (R = 0.52; Dice coefficient = 0.49). Modifying the hypoxic fraction resulted in enhanced mean standardized uptake values for both [(18)F]HX4 and [(18)F]FAZA upon 7% oxygen breathing. Only [(18)F]FMISO uptake was found to be reversible upon exposure to nicotinamide and carbogen.. This study indicates that each tracer has its own strengths and, depending on the question to be answered, a different tracer can be put forward.

Topics: Animals; Cell Hypoxia; Cell Line, Tumor; Computer Simulation; Imidazoles; Misonidazole; Models, Biological; Nitroimidazoles; Oxygen; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Reproducibility of Results; Rhabdomyosarcoma; Sensitivity and Specificity; Triazoles

To investigate the effect of hypoxia tracer properties on positron emission tomography (PET) image quality for three tracers [18F]-fluoromisonidazole (FMISO), [18F]-fluoroazomycinarabinoside (FAZA) and [18F]-flortanidazole (HX4), using mathematical simulations based on microscopic tumor tissue sections.. Oxygen distribution and tracer binding was mathematically simulated on immunohistochemically stained cross-sections of tumor xenografts. Tracer diffusion properties were determined based on available literature. Blood activity and clearance over a four-hour period post-injection (p.i.) were derived from clinical dynamic PET scans of patients suffering from head and neck or bronchial cancer. Simulations were performed both for average patient blood activities and for individual patients, and image contrast between normoxic and hypoxic tissue areas was determined over this four-hour period p.i.. On average, HX4 showed a six-fold higher clearance than FMISO and an almost three-fold higher clearance than FAZA based on the clinical PET data. The absolute variation in clearance was significantly higher for HX4 than for FMISO (standard deviations of 5.75 *10-5 s-1 vs. 1.55 *10-5 s-1). The absolute tracer activity in these scans at four hours p.i. was highest for FMISO and lowest for HX4. Simulated contrast at four hours p.i. was highest for HX4 (2.39), while FMISO and FAZA were comparable (1.67 and 1.75, respectively). Variations in contrast of 7-11% were observed for each tracer depending on the vascularization patterns of the chosen tissue. Higher variations in clearance for HX4 resulted in an increased inter-patient variance in simulated contrast at four hours p.i.. In line with recent experimental and clinical data, the results suggest that HX4 is a promising new tracer that provides high image contrast four hours p.i., though inter-patient variance can be very high. Nevertheless, the widely used tracer FMISO provides a robust and reproducible signal four hours p.i., but with a lower contrast. The simulations revealed tracer clearance to be the key factor in determining image contrast.

Topics: Humans; Hypoxia; Imidazoles; Misonidazole; Models, Theoretical; Nitroimidazoles; Positron-Emission Tomography; Radiopharmaceuticals; Triazoles

Several 2-nitroimidazole-based molecules (NIs) are used as clinical hypoxic tumor radiodiagnostics, but they are not effective as radiosensitizers/radiochemotherapeutics. These NIs permeate tumor cells nonselectively via diffusion, and in therapy, where high doses are required, their dose limiting toxicities preclude success. The synthesis and preliminary in vitro evaluations of three glucoazomycins, members of a novel class of C6-O-glucose-linked-azomycin conjugates that are putative substrates of glucose transport proteins (GLUTs) and possess hypoxia-selective radiosensitization features, are now reported. The hypoxia-dependent upregulation of several GLUTs provides a rational basis to develop these glucoazomycins because more selective uptake in hypoxic cells would decrease systemic toxicities at effective doses. Calculated partition coefficients (ClogP, -1.70 to -2.99) predict rapid in vivo clearance for low systemic toxicity. In vitro experimental data show that glucoazomycins are radiosensitizers and that they competitively inhibit glucose uptake.

Topics: Cell Hypoxia; Cell Line, Tumor; Drug Design; Glucose Transport Proteins, Facilitative; Glucosides; Glycosides; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Misonidazole; Neoplasms; Nitroimidazoles; Radiation-Sensitizing Agents; Radionuclide Imaging; Radiopharmaceuticals; Transcriptional Activation

The study was performed to compare the (18)F-labeled nitroimidazole compound fluoroazomycin arabinoside ((18)F-FAZA) with the standard hypoxia tracer fluoromisonidazole ((18)F-FMISO) in detection of tumor tissue hypoxia and to verify the oxygenation dependency of (18)F-FAZA uptake.. Biodistribution of (18)F-FAZA was studied at various time points in EMT6 tumor-bearing BALB/c mice and in AR42J and A431 tumor-bearing nude mice and compared with that of (18)F-FMISO. The presence of tumor tissue hypoxia was verified in 5 EMT6 and 5 AR42J tumors using an oxygen-sensing needle electrode system. To evaluate the oxygenation dependency of (18)F-FAZA uptake, using the Munich prototype animal PET scanner, 2 serial PET scans were performed in 13 A431 tumor-bearing nude mice breathing pure oxygen or room air on 1 d and then selecting the other oxygen breathing condition on the following day. In addition, digital autoradiography was performed with EMT6 tumor-bearing (18)F-FAZA-dosed, nude mice breathing either room air (n = 8) or carbogen (n = 9).. Tissue partial pressure of oxygen (Po(2)) electrode measurements revealed that tumor hypoxia was present under room air breathing in EMT6 (tissue Po(2) = 2.9 +/- 2.6) and AR42J tumors (tissue Po(2) = 0.4 +/- 0.2), which was significantly lower compared with that of reference tissue (tissue Po(2) = 25.8 +/- 6.7 and tissue Po(2) = 29.0 +/- 3.0 [mean +/- SD], respectively; P < 0.01). In all tumor models, (18)F-FAZA displayed significantly higher tumor-to-muscle and tumor-to-blood ratios compared with (18)F-FMISO, indicating a faster clearance of (18)F-FAZA from normal tissues. In AR42J tumors, (18)F-FAZA tumor-to-normal ratios were found to increase over time. Serial animal (18)F-FAZA PET studies showed that the tumor-to-background ratio was significantly higher in animals breathing room air compared with that of animals breathing pure oxygen (7.3 +/- 2.3 vs. 4.2 +/- 1.2, respectively; P < 0.001). Similarly, autoradiography showed significantly higher tumor-to-muscle ratios in mice breathing room air compared with those of animals breathing carbogen (5.3 +/- 0.8 vs. 2.2 +/- 0.8; respectively; P < 0.02).. (18)F-FAZA shows superior biokinetics and is, thus, a promising PET tracer for the visualization of tumor hypoxia. This study also verified a hypoxia-specific uptake mechanism for (18)F-FAZA in murine tumor models.

Topics: Animals; Cell Hypoxia; Disease Models, Animal; Female; Metabolic Clearance Rate; Mice; Mice, Inbred BALB C; Mice, Nude; Misonidazole; Neoplasms; Nitroimidazoles; Organ Specificity; Oxidation-Reduction; Oxygen; Radionuclide Imaging; Radiopharmaceuticals; Tissue Distribution