• Nuclear Medicine and Molecular Imaging
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• v.40 no.5
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• pp.263-270
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• 2006

Purpose: Several radioisotope-labeled thymidine derivatives such as $[^{11}C]$thymidine was developed to demonstrate cell proliferation in tumor. But it is difficult to track metabolism with $[^{11}C]$thymidine due to rapid in vivo degradation and its short physical half-life. 3'-$[^{18}F]$fluoro-3'-deoxythymidine ($[^{18}F]$FLT) was reported to have the longer half life of fluorine-18 and the lack of metabolic degradation in vivo. Here, we described the synthesis of the 3'-$[^{18}F]$fluoro-3'-deoxythymidine ($[^{18}F]$FLT) and compared with $([^{18}F]FET)\;and\;([^{18}F]FDG)$ in cultured 9L cell and obtained the biodistribution and PET image in 9L tumor hearing rats. Material and Methods: For the synthesis of $[^{18}F]$FLT, 3-N-tert-butoxycarbonyl-(5'-O-(4,4'-dimet hoxytriphenylmethyl)-2'-deoxy-3'-O-(4-nitrobenzenesulfonyl)-${\beta}$-D-threopentofuranosyl)thymine was used as a FLT precursor, on which the tert-butyloxycarbonyl group was introduced to protect N3-position and nitrobenzenesulfonyl group. Radiolabeling of nosyl substitued precursor with $^{18}F$ was performed in acetonitrile at $120^{\circ}C$ and deproteced with 0.5 N HCI. The cell uptake was measured in cultured 9L glioma cell. The biodistribution was evaluated in 9L tumor bearing rats after intravenous injection at 10 min, 30 min, 60 min and 120 min and obtained PET image 60 minutes after injection. Results: The radiochemical yield was about 20-30% and radiochemical purity was more than 95% after HPLC purification. Cellular uptake of $[^{18}F]$FLT was increased as time elapsed. At 120 min post-injection, the ratios of tumor/blood, tumor/muscle and tumor/brain were $1.61{\pm}0.34,\;1.70{\pm}0.30\;and\;9.33{\pm}2.22$, respectively. The 9L tumor was well visualized at 60 min post injection in PET image. Conclusion: The uptake of $[^{18}F]$FLT in tumor was higher than in normal brain and PET image of $[^{18}F]$FLT was acceptable. These results suggest the possibility of $[^{18}F]$FLT at an imaging agent for brain tumor.

• Nuclear Medicine and Molecular Imaging
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• v.43 no.6
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• pp.535-542
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• 2009

Purpose: This study was performed to know whether [$^{18}F$]Fluorothymidine (FLT) positron emission tomography (PET) can be used to monitor early response to radiotherapy in comparison with [$^{18}F$]Fluorodeoxyglucose (FDG) PET, and to establish the optimal imaging time for prediction of therapy response. Materials and Methods: Two patients with nasopharyngeal cancer underwent serial FLT PET and FDG PET before and during radiotherapy. Three on-treatment FLT and FDG PET scans were performed on 1 week, 2 weeks and 3 weeks (at each time of 10 Gy, 20 Gy and 30 Gy delivered). The peak standardized uptake values ($SUV_{peak}$) of primary tumors were measured on FLT and FDG PET. Then, percent changes of $SUV_{peak}$ after therapy were calculated. Results: In two patients, baseline values of $SUV_{peak}$ on FDT PET were higher than those on FLT PET (FLT vs FDG; 3.7 vs 5.0, and 5.7 vs 15.0). In patient 1, FLT $SUV_{peak}$ showed 78%, 78% and 84% of decrease on 1 week, 2 and 3 weeks after treatment, whereas FDG $SUV_{peak}$ showed 18%, 52% and 66% of decrease, respectively. In patient 2, FLT $SUV_{peak}$ showed 75%, 75% and 68% of decrease, whereas FDG $SUV_{peak}$ showed 51%, 49% and 58% of decrease, respectively. Both patients reached to complete remission after radiotherapy. Conclusion: After radiotherapy, the decrease of FLT tumor uptake preceded the decrease of FDG tumor uptake in patients with nasopharyngeal cancer, and 1 week after therapy may be appropriate time for the assessment of early response. FLT PET might be more useful than FDG PET for monitoring early response to radiotherapy.

• Nuclear Medicine and Molecular Imaging
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• v.42 no.1
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• pp.29-38
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• 2008

Purpose: The aim of this study was to investigate the feasibility of 3 ' -[F-18]fluoro-3 ' -deoxythymidine positron emission tomography(FLT-PET) for the detection of locally advanced breast cancer and to compare the degree of FLT and 2' -deoxy-2 ' -[F-18]fluoro-d-glucose(FDG) uptake in primary tumor, lymph nodes and other normal organs. Material & Methods: The study subjects consisted of 22 female patients (mean age; $42{\pm}6$ years) with biopsy-confirmed infiltrating ductal carcinoma between Aug 2005 and Nov 2006. We performed conventional imaging workup, FDG-PET and FLT PET/CT. Average tumor size measured by MRI was $7.2{\pm}3.4$ cm. With visual analysis, Tumor and Lymph node uptakes of FLT and FDG were determined by calculation of standardized uptake value (SUV) and tumor to background (TB) ratio. We compared FLT tumor uptake with FDG tumor uptake. We also investigated the correlation between FLT tumor uptake and FDG tumor uptake and the concordant rate with lymph node uptakes of FLT and FDG. FLT and FDG uptakes of bone marrow and liver were measured to compare the biodistribution of each other. Results: All tumor lesions were visually detected in both FLT-PET and FDG-PET. There was no significant correlation between maximal tumor size by MRI and SUVmax of FLT-PET or FDG-PET (p>0.05). SUVmax and $$SUV_{75} (average SUV within volume of interest using 75% isocontour) of FLT-PET were significantly lower than those of FDG-PET in primary tumor (SUVmax; $6.3{\pm}5.2\;vs\;8.3{\pm}4.9$, p=0.02 /$SUV_{75};\;5.3{\pm}4.3\;vs\;6.9{\pm}4.2$, p=0.02). There is significant moderate correlation between uptake of FLT and FDG in primary tumor (SUVmax; rho=0.450, p=0.04 / SUV75; rho=0.472, p=0.03). But, TB ratio of FLT-PET was higher than that of FDG-PET($11.7{\pm}7.7\;vs\;6.3{\pm}3.8$, p=0.001). The concordant rate between FLT and FDG uptake of lymph node was reasonably good (33/34). The FLT SUVs of liver and bone marrow were $4.2{\pm}1.2\;and\;8.3{\pm}4.9$. The FDG SUVs of liver and bone marrow were $1.8{\pm}0.4\;and\;1.6{\pm}0.4$. Conclusion: The uptakes of FLT were lower than those of FDG, but all patients of this study revealed good FLT uptakes of tumor and lymph node. Because FLT-PET revealed high TB ratio and concordant rate with lymph node uptakes of FDG-PET, FLT-PET could be a useful diagnostic tool in locally advanced breast cancer. But, physiological uptake and individual variation of FLT in bone marrow and liver will limit the diagnosis of bone and liver metastases.

• Bulletin of the Korean Chemical Society
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• v.33 no.7
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• pp.2177-2180
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• 2012

New [$^{18}F$]F-fluorination methods using a minimized amount of precursor has been developed by controlling the base concentration. In the first method, pre-conditioning of the anion exchange cartridge with $K_2CO_3$ solution or water was carried out. The trapped [$^{18}F$]fluoride on the cartridge was then eluted by KOMs or KOTf solution. [$^{18}F$]F-Fluorination could be performed without additional base. In the second method, the QMA cartridge was preconditioned with KOMs solutions. Trapped [$^{18}F$]fluoride on the QMA was then eluted with KOMs and additional base, such as KOH, $K_2CO_3$, and $KHCO_3$, was added into the reaction vessel. Method 1 showed a [$^{18}F$]F-incorporation yield of 20.9% for [$^{18}F$]FLT synthesis with 5 mg of precursor. Unlike method 1, a [$^{18}F$]F-incorporation yield of 91.4% was achieved from the same amount of precursor in method 2.

• The Korean Journal of Nuclear Medicine
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• v.38 no.2
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• pp.198-204
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• 2004

Tumor cell proliferation is considered to be a useful prognostic indicator of tumor aggressiveness and tumor response to therapy but in vitro measurement of individual proliferation is complex and tedious work. PET imaging provides a noninvasive approach to measure tumor growth rate in situ. Early approaches have used $^{18}F$-FDG or methionine to monitor proliferation status. These 2 tracers detect changes in glucose and amino acid metabolism, respectively, and therefore provide only an indirect measure of proliferation status. More recent studies have focused on DNA synthesis itself as a marker of cell proliferation. Cell lines and tissues with a high proliferation rate require high rates of DNA synthesis. $[^{11}C]Thymidine$ was the first radiotracer for noninvasive imaging of tumor proliferation. The short half-life of $^{11}C$ and rapid metabolism of $[^{11}C]Thymidine$ in vivo make the radiotracer less suitable for routing use. Halogenated thymidine analogs such as 5-iodo-2-deoxyuridine (IUdR) can be successfully used as cell proliferation markers for in vitro studies because these compounds are rapidly incorporated into newly synthesized DNA. IUdR has been evaluated as a potential in vivo tracer in nuclear medicing but the image qualify and the calculation of proliferation rates are impaired by its rapid in vivo degradation. Hence, the thymidine analog $3'-deoxy-3'-^{18}F-fluorothymidine$ (FLT) was recently introduced as a stable proliferation marker with a suitable nuclide half-life and stable in vivo. $[^{18}F]FLT$ is phosphorylated to 3-fluorothymidine monophosphate by thymidine kinase 1 and reflects thymidine kinase 1 activity in proliferating cell. $[^{18}F]FLT$ PET is feasible in clincal use and well correlates with cellular proliferation. Choline is a precursor for the biosynthesis of phospholipids (in particular, phosphatidylcholine), which is the essential component of all eukaryotic cell membranes and $[^{11}C]choline$, which is a new marker for cellular proliferation.

• 대한핵의학회:학술대회논문집
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• 2004.11a
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• pp.412.1-412.1
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• 2004

• 대한핵의학회:학술대회논문집
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• 2003.11a
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• pp.11.1-11.1
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• 2003

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5341-5344
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• 2013

Objectives: To explore the relationships between age, cytogenetic subgroups, molecular markers, and cells with leukemic aberrant immunophenotype in patients with acute myeloid leukemia (AML). Methods: In this study, we evaluated the correlations between age, cytogenetic subgroups (normal, balanced and unbalance karyotype), molecular mutations (NPM1, FLT3-ITD, and CEBPA mutations) and marrow leukemia cells (LC) identified by flow cytometry in 256 patients with de novo AML. Results: From age group 10-19 years to age group ${\geq}60$ years, the percentage of LC decreased from $67.0{\pm}18.4%$ to $49.0{\pm}25.1%$ (F=2.353, P=0.041). LC percentage was higher in patients with balanced karyotypes ($65.7{\pm}22.4%$), than those with unbalanced karyotypes ($46.0{\pm}26.6%$) (u=3.444, P=0.001) or a normal karyotype ($49.9{\pm}22.1%$) (u=5.093, P<0.001). Patients with FLT3-ITD ($64.3{\pm}19.5%$) had higher LC percentages compared with those without ($54.2{\pm}24.3%$) (u=2.794, P=0.007). Conclusions: Associations between age, cytogenetics, molecular markers, and marrow leukemia cells may offer beneficial information to understand the biology and pathogenesis of AML.

• 대한핵의학회:학술대회논문집
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• 2004.11a
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• pp.401.1-401.1
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• 2004

• Nuclear Medicine and Molecular Imaging
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• v.43 no.2
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• pp.91-99
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• 2009

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 $^{18}F$-fluorine. In this review we describe recent methods and novel trends for the introduction of $^{18}F$-fluorine into molecules which in turn are intended to serve as imaging agents for PET study. Nucleophilic $^{18}F$-fluorination of some halo- and mesyloxyalkanes to the corresponding $^{18}F$-fluoroalkanes with $^{18}F$-fluoride obtained from an $^{18}O(p,n)^{18}F$ reaction, using novel reaction media system such as an ionic liquidor tert-alcohol, has been studied as a new method for $^{18}F$-fluorine labeling. Ionic liquid method is rapid and particularly convenient because $^{18}F$-fluoride in $H_2O$ 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 $^{18}F$-fluorine for PETimaging, and it is illustrated by the synthesis of $^{18}F$-fluoride radiolabeled molecular imaging probes, such as $^{18}F$-FDG, $^{18}F$-FLT, $^{18}F$-FP-CIT, and $^{18}F$-FMISO, in high yield and purity and in shorter times compared to conventional syntheses.