Nucleophilic Fluorination Reactions in Novel Reaction Media for 18F-Fluorine Labeling Method / 핵의학분자영상

Noninvasive imaging of molecular and biological processes in living subjects with positron emission tomography (PET) provides exciting opportunities to monitor metabolism and detect diseases in humans. Measuring these processes with PET requires the preparation of specific molecular imaging probes labeled with 18F-fluorine. In this review we describe recent methods and novel trends for the introduction of 18F-fluorine into molecules which in turn are intended to serve as imaging agents for PET study. Nucleophilic 18F-fluorination of some halo- and mesyloxyalkanes to the corresponding 18F-fluoroalkanes with 18F-fluoride obtained from an 18O(p,n)18F reaction, using novel reaction media system such as an ionic liquidor tert-alcohol, has been studied as a new method for 18F-fluorine labeling. Ionic liquid method is rapid and particularly convenient because 18F-fluoride in H2O can be added directly to the reaction media, obviating the careful drying that is typically required for currently used radiofluorination methods. The nonpolar protic tert-alcohol enhances the nucleophilicity of the fluoride ion dramatically in the absence of any kind of catalyst, greatly increasing the rate of the nucleophilic fluorination and reducing formation of byproducts compared with conventional methods using dipolar aprotic solvents. The great efficacy of this method is a particular advantage in labeling radiopharmaceuticals with 18F-fluorine for PETimaging, and it is illustrated by the synthesis of 18F-fluoride radiolabeled molecular imaging probes, such as 18F-FDG, 18F-FLT, 18F-FP-CIT, and 18F-FMISO, in high yield and purity and in shorter times compared to conventional syntheses

Effect of Combination of Anticancer Agents and Nitroimidazoles on the Survival of Human Hepatocellular Carcinoma Cells under Hypoxic Conditions

PURPOSE: In a previous study, we have shown that anticancer agents inhibiting topoisomerases improve survival of tumor cells under hypoxic condition. In the present study, we evaluated whether and how cell survival effect of the anticancer agents under hypoxic conditions could be eliminated by the addition of nitroimidazoles, a class of bioreductive agents. METHODS: Human hepatocellular carcinoma cells (HepG2) were incubated with different combinations of pimonidazole (1~1,000 microg/ml) and doxorubicin (0.1 or 1 microg/ml) concentrations under different O2 concentrations [1, 3, 5, 10 and 21 O2]. Then cell numbers, glucose concentrations and lactic acid concentrations in the medium were measured, and DNA fragmentation assay was performed. Finally, different combinations of nitroimidazoles, such as pimonidazole, misonidazole, etanidazole, tinidazole, metronidazole, ornidazole or dimetridazole, and anticancer agents, such as doxorubicin, campothecin, epirubicin, dactinomycin, etoposide or mitomycin C was added to the cell culture medium under hypoxic conditions (1% O2). RESULTS: Pimonidazole at a concentration of 100 microg/ml eliminated cell survival effect of doxorubicin at the concentrations of 0.1 and 1 microg/ml under hypoxic condition (1% O2) by promoting apoptosis. Almost all the cells died even after 24 hours of incubation for all the oxygen concentrations at a combination of 100 microg/ml pimonidazole and 1 microg/ml doxorubicin. Finally, pimonidazole at a concentration of 100 microg/ml, and misonidazole or etanidazole at a concentration of 1,000 microg/ml eliminated cell survival effect of all the anticancer agents tested under hypoxic condition. CONCLUSION: Combination therapy of doxorubicin (adriamycin) with pimonidazole can maximize dororubicin efficacy by eliminating cell survival effect of doxorubicin under hypoxic conditions in treating solid tumors, such as breast cancer.

Biodistribution of Iodine-131-Iodomisonidazole and Imaging of Tumor Hypoxia in Mice bearing CT-26 Adenocarcinoma / 대한핵의학회잡지

urpose: Misonidazole is a radiosensitizer that binds in hypoxic cells. The purpose of this study was to find out the feasibility of I-131-Iodomisonidazole (IMISO) for imaging of tumor hypoxia. MATERIALS AND METHODS: Tosyl precursor was dissolved in acetonitrile and I-131-NaI was added to synthesize IMISO. Balb/c mice inoculated with CT-26 adenocarcinoma were injected with IMISO. Mice were sacrificed at 1,2,4,24 hr and % of injected dose per gram of tissue (%ID/g) was determined. For scintigraphy and MRI, mouse bearing CT-26 adenocarcinoma was administered with IMISO and imaging was performed 4 hr after. Then, mouse body was fixed and microtomized slice was placed on radiographic film for autoradiography. RESULTS: %ID/g of tumor was 1.64 (1h), 0.98 (2h), 0.85 (4h) and 0.20 (24h), respectively. At 24h, %ID/g of tumor was higher than that of all other tissues except thyroid. Tumor to muscle ratio increased with time and tumor to blood ratio also increased with time and reached 1.53 at 24 hr. On autoradiogram, tumor was well visualized as an increased activity in central hypoxic area of the tumor which corresponds to the area of high signal intensity on T2-weighted MR image. On scintigraphy, tumor uptake was visualized. CONCLUSION:: This RESULTS suggest that IMISO may have a potential for tumor hypoxia imaging in mouse model. However, further study is needed to improve it's localization in tumor tissue and to achieve acceptable images of tumor hypoxia.

In vivo radiosensitization of nitroimidazole derivative [KIN-804] compared with misonidazole [MISO]

The effects of a single dose of KIN-804 and MISO on liver and Ehrlich solid carcinoma [ESC] have been studied in Swiss albino mice. KIN-804 and MISO were administered at doses of 800 and 400 mg/Kg body weight, respectively. Liver glucose-6-phosphatase [G-6-pase], glutathione content and superoxide dismutase of ESC, were measured at different times from drug administration. [G-6-pase] was elevated significantly 24 hours after MISO only, while GSH and SOD showed nearly the same changes after MISO and KIN 804. Therefore, KIN-804 is a less toxic radiosensitizer and should be implicated in clinical trials

Chemical radiosensitization by misonidazole: production and repair of DNA single-strand breaks in Yoshida ascites tumor cells.

Formation of strand-breaks in DNA and its repair in Yoshida ascites tumor cells exposed to gamma radiation (100-400 Gy) in presence and absence of misonidazole (10 mM) were studied. The methodology involved pre-labelling of cellular DNA by 3H-thymidine during cell proliferation in rats, irradiation of cells in vitro and analysing sedimentation profile of DNA by ultracentrifugation in alkaline sucrose density gradients. Irradiation under euoxic conditions resulted in formation of about 1.5 times greater number of strand breaks as compared to those formed during irradiation under hypoxic conditions. Misonidazole (10 mM) by its presence along with the cells during irradiation under hypoxic conditions caused a 3-fold increase in the number of single strand breaks, but under euoxic conditions of irradiation the presence of misonidazole did not enhance the strand break formation. Incubation of cells irradiated in absence of misonidazole for 1 hr in tissue culture medium at 37 degrees C resulted in repair of substantial fraction of the strand breaks while there was no repair of the DNA strand breaks in cells irradiated in the presence of the chemical.

Radiotherapy of the Malignant Gliomas

The outlook for patients with malignant gliomas of the brain remains rather poor. However, after many experience of decades, the data indicate that some improvements seemed to have occurred with following adjuvant treatments after surgery; 1) High dose post-operative radiation therapy 6000-7000 rad/7-8 week. 2) High dose irradiation with BCNU combined therapy(ECOG). 3) Multiple daily fractionated radiotherapy combined with or without misonidazole. 4) Intracranial implant or intraoperative electron therapy.