Evaluation of 99mTc-MAG3-2-nitroimidazole for hypoxic tumor imaging

Yun Sang Lee,Young Joo Kim,Jae Min Jeong 대한방사성의약품학회 2019 Journal of radiopharmaceuticals and molecular prob Vol.5 No.1

2-Nitroimidazole derivatives have been reported to accumulate in hypoxic tissue. We prepared a novel 99mTc-MAG3-2-nitroimidazole and evaluated the feasibility for hypoxia imaging agent. Bz-MAG3-2-nitroimidazole wassynthesized by direct coupling of Bz-MAG3 and 2-nitroimidazole using dicyclohexylcarbodiimide. Bz-MAG3-2-nitroimidazole was labeled with 99mTc in the presence of tartaric acid and SnCl2-2H2O at 100°C for 30 min. And the reaction mixture was purified by C18 Sep-pak cartridge. The labeling efficiency and the radiochemicalpurity were checked by ITLC-SG/acetonitrile. The tumor was grown in balb/c mice for 8~13 days after thesubcutaneous injection of tumor cells, CT-26 (murine colon adenocarcinoma cell). Biodistribution study andtumor autoradiography were performed in the xenografted mice after i.v injection of 74 kBq/0.1 mL and 19MBq/0.1 mL of 99mTc-MAG3-2-nitroimidazole, respectively. In vivo images of 99mTc-MAG3-2-nitroimidazolein tumor bearing mice were obtained 1.5 hr post injection. The labeling efficiency was 45±20% and theradiochemical purity after purification was over 95%. Paper electrophoresis confirmed negative charge of99mTc-MAG3-2-nitroimidazole. 99mTc-MAG3-2-nitroimidazole was very stable at room temperature and its proteinbinding was 53%. The 99mTc-MAG3-2-nitroimidazole exhibited high uptake in the liver, stomach and intestine. In biodistribution study using tumor bearing mice, the uptakes (% ID/g) of the tumor were 0.5±0.1, 0.4±0.0,0.2±0.1 and 0.1±0.1 at 5, 15, 30 min and 4 hrs. Tumor/muscle ratio were 1.4±0.1, 2.2±0.83, 3.0±0.9, and 3.7(n=2) for 5, 15, 30 min and 4 hrs. The uptake in hypoxic area was found higher than in non-hypoxic area oftumor tissue by autoradiography. In vivo images showed the relatively faint uptake to the hypoxic tumor region. 99mTc-MAG3-2-nitroimidazole was successfully synthesized and found feasible for imaging hypoxia

Synthesis and biodistribution of 18F-labeled α-, β- and ω-fluorohexadecanoic acid

Yun-Sang Lee,Young Joo Kim,Gi Jeong Cheon,Jae Min Jeong 대한방사성의약품학회 2018 Journal of radiopharmaceuticals and molecular prob Vol.4 No.2

ω-[18F]-Fluorohexadecanoic acid (FHA) has been used for imaging of fatty acid metabolism of myocardium. To increase retention of radiolabeled fatty acid by blocking β-oxidation, methyl branched analogues have been used. In this experiment, we tried to synthesize 18F-labeled α-, β- and ω-FHA for imaging of the myocardial fatty acid metabolism. We synthesized α-, β- and ω-mesylated methyl hexadecanoates and labeled with 18F by reacting with [18F]TBAF in acetonitrile at 80ºC for 10 min. Methyl ester group was removed by 1 M NaOH at 80ºC for 5 min. The yields of α-[18F] and ω-[18F]FHA were 25.5 and 45.5%, respectively [EOS]. However, β-[18F] FHA was not labeled at all due to a fast elimination reaction. The biodistribution study in ICR-mice showed that ω-[18F]FHA has higher myocardial uptake and lower liver uptake than α-[18F]FHA. The electron-withdrawing effect of fluorine at α- position is believed to be the major factor affecting the biodistribution

Evaluation of ^99mTc-MAG₃-2-nitroimidazole for hypoxic tumor imaging

Lee, Yun-Sang,Kim, Young Joo,Jeong, Jae Min Korean Society of Radiopharmaceuticals and Molecul 2019 Journal of radiopharmaceuticals and molecular prob Vol.5 No.1

2-Nitroimidazole derivatives have been reported to accumulate in hypoxic tissue. We prepared a novel $^{99m}Tc-MAG_3$-2-nitroimidazole and evaluated the feasibility for hypoxia imaging agent. $Bz-MAG_3$-2-nitroimidazole was synthesized by direct coupling of $Bz-MAG_3$ and 2-nitroimidazole using dicyclohexylcarbodiimide. $Bz-MAG_3$-2-nitroimidazole was labeled with $^{99m}Tc$ in the presence of tartaric acid and $SnCl_2-2H_2O$ at $100^{\circ}C$ for 30 min. And the reaction mixture was purified by $C_{18}$ Sep-pak cartridge. The labeling efficiency and the radiochemical purity were checked by ITLC-SG/acetonitrile. The tumor was grown in balb/c mice for 8~13 days after the subcutaneous injection of tumor cells, CT-26 (murine colon adenocarcinoma cell). Biodistribution study and tumor autoradiography were performed in the xenografted mice after i.v injection of 74 kBq/0.1 mL and 19 MBq/0.1 mL of $^{99m}Tc-MAG_3$-2-nitroimidazole, respectively. In vivo images of $^{99m}Tc-MAG_3$-2-nitroimidazole in tumor bearing mice were obtained 1.5 hr post injection. The labeling efficiency was $45{\pm}20%$ and the radiochemical purity after purification was over 95%. Paper electrophoresis confirmed negative charge of $^{99m}Tc-MAG_3$-2-nitroimidazole. $^{99m}Tc-MAG_3$-2-nitroimidazole was very stable at room temperature and its protein binding was 53%. The $^{99m}Tc-MAG_3$-2-nitroimidazole exhibited high uptake in the liver, stomach and intestine. In biodistribution study using tumor bearing mice, the uptakes (% ID/g) of the tumor were $0.5{\pm}0.1$, $0.4{\pm}0.0$, $0.2{\pm}0.1$ and $0.1{\pm}0.1$ at 5, 15, 30 min and 4 hrs. Tumor/muscle ratio were $1.4{\pm}0.1$, $2.2{\pm}0.83$, $3.0{\pm}0.9$, and 3.7 (n=2) for 5, 15, 30 min and 4 hrs. The uptake in hypoxic area was found higher than in non-hypoxic area of tumor tissue by autoradiography. In vivo images showed the relatively faint uptake to the hypoxic tumor region. $^{99m}Tc-MAG_3$-2-nitroimidazole was successfully synthesized and found feasible for imaging hypoxia.

Synthesis and biodistribution of ¹⁸F-labeled α-, β- and ω-fluorohexadecanoic acid

Lee, Yun-Sang,Kim, Young Joo,Cheon, Gi Jeong,Jeong, Jae Min Korean Society of Radiopharmaceuticals and Molecul 2018 Journal of radiopharmaceuticals and molecular prob Vol.4 No.2

${\omega}-[^{18}F]$-Fluorohexadecanoic acid (FHA) has been used for imaging of fatty acid metabolism of myocardium. To increase retention of radiolabeled fatty acid by blocking ${\beta}$-oxidation, methyl branched analogues have been used. In this experiment, we tried to synthesize 18F-labeled ${\alpha}-$, ${\beta}-$ and ${\omega}-FHA$ for imaging of the myocardial fatty acid metabolism. We synthesized ${\alpha}-$, ${\beta}-$ and ${\omega}$-mesylated methyl hexadecanoates and labeled with $^{18}F$ by reacting with $[^{18}F]$TBAF in acetonitrile at $80^{\circ}C$ for 10 min. Methyl ester group was removed by 1 M NaOH at $80^{\circ}C$ for 5 min. The yields of ${\alpha}-[^{18}F]$ and ${\omega}-[^{18}F]FHA$ were 25.5 and 45.5%, respectively [EOS]. However, ${\beta}-[^{18}F]FHA$ was not labeled at all due to a fast elimination reaction. The biodistribution study in ICR-mice showed that ${\omega}-[^{18}F]FHA$ has higher myocardial uptake and lower liver uptake than ${\alpha}-[^{18}F]FHA$. The electron-withdrawing effect of fluorine at ${\alpha}-$ position is believed to be the major factor affecting the biodistribution.

A study of ^99mTc-sestamibi labeling condition using radio-chromatography

Moon, Sung-Hyun,Lee, Yun-Sang,Lee, Dong Soo,Chung, June-Key,Jeong, Jae Min Korean Society of Radiopharmaceuticals and Molecul 2017 Journal of radiopharmaceuticals and molecular prob Vol.3 No.1

Tc-99m labeled sestamibi ($^{99m}Tc$-MIBI) is one of most widely used radiopharmaceuticals for myocardial SPECT imaging. Radiolabeling of $^{99m}Tc$-MIBI is recommended by heating in $100^{\circ}C$ water bath for 15 min. However, the water bath might be a source of contamination. Thus, if radiolabeling of $^{99m}Tc$-sestamibi can be performed at room temperature, then it would be more convenient to use in clinical application. In this study, we performed the radiolabeling of $^{99m}Tc$-MIBI in different temperature conditions or using different instruments to find out the efficient labeling condition. We studied the $^{99m}Tc$-MIBI labeling at room temperature or $100^{\circ}C$ heating block, and checked the labelling yields every 1 min for 10 min using radio-TLC with 2 different eluents-saline and acetone. From the experiment, we confirmed that the $^{99m}Tc$-MIBI can be labeled over 90% yield but not completed at room temperature. However, the $^{99m}Tc$-MIBI labeling was completed when it was performed in the $100^{\circ}C$ heating block. Finally, we proved that heating is essential for complete $^{99m}Tc$-MIBI labelling, furthermore using heating block is also possible instead of water bath.

Microfluidic generation of Prussian blue-laden magnetic micro-adsorbents for cesium removal

Kang, Sung-Min,Rethinasabapathy, Muruganantham,Hwang, Seung Kuy,Lee, Go-Woon,Jang, Sung-Chan,Kwak, Cheol Hwan,Choe, Sang-Rak,Huh, Yun Suk Elsevier 2018 CHEMICAL ENGINEERING JOURNAL -LAUSANNE- Vol.341 No.-

<P><B>Abstract</B></P> <P>Here, we designed and synthesized a recoverable multifunctional adsorbent using a microfluidic reaction system and evaluated the removal performance of the smart adsorbent toward radioactive cesium as a model sample. Prussian blue-laden magnetic micro-adsorbents (PB-MNPs-MAs) with uniform morphology and monodispersity were generated via two-step sequential procedures using a glass capillary microfluidic system, followed by chemical co-precipitation with a high production rate. The cesium removal efficacy of the PB-MNPs-MAs was analyzed based on Langmuir and Freundlich isotherms by controlling adsorption parameters such as adsorbent size, initial cesium concentration, and contact time. The adsorption isotherm of the PB-MNPs-MAs was better fitted to the Langmuir model with a maximum cesium adsorption capacity of 58.73 mg g<SUP>−1</SUP>, which was 40% higher than that of macro-adsorbents in a dynamic magnetic field. This result can be attributed to their large specific area, which increased the kinetic rate of cesium adsorption and achieved saturation within 20 min. Additionally, the PB-MNPs-MAs were recovered from wastewater within 5 s under a static magnetic field, indicating their great potential for magnetic actuation. We believe that our PB-MNPs-MAs can encapsulate nano-functional adsorbents and prevent actuation, making them promising for environmental remediation and especially for removal of radionuclides.</P> <P><B>Highlights</B></P> <P> <UL> <LI> PB-MNPs-MAs were generated in microfluidic device using chemical co-precipitation. </LI> <LI> The prepared PB-MNPs-MAs are monodispersed with uniform morphology. </LI> <LI> PB-MNPs-MAs exhibited high Cs adsorption capacity (58.73 mg g<SUP>−1</SUP>). </LI> <LI> 100% recovery of PB-MNPs-MAs is possible under static magnetic field after Cs adsorption. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Biodistribution and PET imaging of [¹⁸F]FMISO in mousecolon cancer xenografted mice

Seelam, Sudhakara Reddy,Lee, Ji Youn,Kim, Young Joo,Lee, Yun-Sang,Jeong, Jae Min Korean Society of Radiopharmaceuticals and Molecul 2015 Journal of radiopharmaceuticals and molecular prob Vol.1 No.2

Hypoxia is an important adverse prognostic factor for tumor progression and is a major cause of failure of radiation therapy. In case of short-term hypoxia, the metabolism can recover to normal, but if hypoxia persists, it causes irreversible cell damage and finally leads to death. So a hypoxia marker would be very useful in oncology. In particular, 2-nitroimidazole can be reduced to form a reactive chemical species, which can bind irreversibly to cell components in the absence of sufficient oxygen, thus, the development of radiolabeled nitroimidazole derivatives for the imaging of hypoxia remains an active field of research to improve cancer therapy result. 2-nitroimidazole based hypoxia marker, [$^{18}F$]FMISO holds promise for the evaluation of tumor hypoxia by Positron emission tomography (PET), at both global and local levels. In the present study, [$^{18}F$]FMISO was synthesized using an automatic synthesis module with high radiochemical purity (>99%) in 60 min. Immunohistochemical analysis using pimonidazole confirmed the presence of hypoxia in xenografted CT-26 tumor tissue. A biodistribution study in CT-26 xenografted mice showed that the increased tumor-to-muscle ratio and tumor-to-blood ratios from 10 to 120 min post-injection. In the PET study, [$^{18}F$]FMISO also showed increased tumor-to-muscle ratios from 10 to 120 min post-injection. In conclusion, this study demonstrates the feasibility and utility of [$^{18}F$]FMISO for imaging hypoxiain mouse colon cancer model using small animal PET.

Loop와 HPLC Purification 방법보다 더 높은 비방사능을 보여주는 카트리지 Methylation과 Purification을 이용한 손쉬운 [ ¹¹C]PIB 합성

이용석,조용현,이홍재,이윤상,정재민,Lee, Yong-Seok,Cho, Yong-Hyun,Lee, Hong-Jae,Lee, Yun-Sang,Jeong, Jae Min 대한핵의학기술학회 2018 핵의학 기술 Vol.22 No.2

$[^{11}C]PIB$는 베타아밀로이드($A{\beta}\;plague$)라는 변성 단백질에 결합하여 뇌의 기능과 기억력을 서서히 감퇴시키는 비가역적인 질환인 치매를 조기에 감별할 수 있는 대표적인 방사성의약품이다. 지금까지 많은 실험실에서 $[^{11}C]PIB$는 자동화합성장치에서 $[^{11}C]methyl\;iodide$나 $[^{11}C]methyl\;triflate$를 만든 다음 loop나 vial 방법을 사용하여 methylation을 한 다음 HPLC로 정제를 하는 것이다. 하지만 기존의 보고된 방법은 시간이 오래 걸리며, HPLC와 같은 복잡한 시스템을 필요로 하여 소규모 실험실에서 합성하기에 적합하지 않으며, 최종 product에서 에탄올 함량이 높다는 단점이 있었다. 이러한 단점을 보완하기 위하여 카트리지만을 사용하여 카트리지에서 methylation과 purification을 동시에 실시함으로써 합성 시간을 단축하고, 비방사능이 높고, 낮은 에탄올 함량을 가진 $[^{11}C]PIB$를 합성 가능한지 확인하고자 하였다. 가장 널리 사용하는 카트리지 6종(CM, HLB, Alumina, C18, tC18, tC18 environmental을 선택하여 screening test를 실시하였다. 6-OH-BTA-0 1 mg을 c-HXO에 녹인 다음 6개의 카트리지에 loading를 한 다음 0.5 M MSP(pH 5.1) 20 mL로 정제를 한 다음 최종 fraction을 받아서 analytical HPLC로 전구체 잔류량을 측정한 결과 hydrophobicity가 낮은 계열(CM, HLB, Alumina)의 카트리지에서는 완충액으로 정제를 하였을 때 잔류전구체의 양이 많았으나, 탄소함량이 많은 계열의 카트리지(C18, tC18, tC18 environmental)에서는 잔류전구체의 양이 CM, HLB, Alumina 카트리지에 비하여 상대적으로 적었다. 완충액의 정제 농도와 부피를 최적화 하기 위하여 screening test에서 가장 좋은 결과를 나타낸 C18 series cartridge를 가지고 추가 실험을 진행하였다. 인산완충액 농도를 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 250 mM, 500 mM로 변화시켰으며, 에탄올 함량은 20%와 30%로 하여 용출액을 분석하여서, $[^{11}C]PIB$를 카트리지로 합성하기 위한 최적의 조합은 tC18 environmental cartridge와 0.5 M MSP 20 mL인 것을 알 수 있었다. 기존에 보고된 방법과 cartridge를 비교한 결과, 합성시간에서는 각각 15 ~ 18min, 8 ~ 9 min이 소요되었으며, product activity는 각각 $4.1{\pm}1.4\;GBq$ (n=41), $3.8{\pm}0.9\;GBq$ (n=3), 방사화학적 수율(based on HPLC analysis of the crude product)에서는 $13.9{\pm}4.4%$ (n=41), $12.3{\pm}2.2%$ (n=3)로 별다른 차이가 없었으며, 비방사능에 있어서는 HPLC purification method가 $78.7{\pm}39.7\;GBq/{\mu}mol$ (n=41), cartridge method가 $420.6{\pm}20.4\;GBq/{\mu}mol$ (n=3)로 카트리지 방법이 기존 방법보다 더 좋은 결과를 나타내었다. 또한, 잔류 용매(c-HXO)도 vial or loop method와 별다른 차이가 없었으며, 에탄올 함량에 있어서는 70%(기존 방법)에서 30%(카트리지 방법)로 두 배 이상 함량이 적다는 사실을 알 수 있었다. 지금까지 알아본바와 같이 cartridge method는 reported method(HPLC purification)에 비하여 더 향상된 결과를 보여준다는 사실을 확인하였다. $[^{11}C]PIB$ synthesis has been performed by a loop-methylation and HPLC purification in our lab. However, this method is time-consuming and requires complicated systems. Thus, we developed an on-cartridge method which simplified the synthetic procedure and reduced time greatly by removing HPLC purification step. We compared 6 different cartridges and evaluated the $[^{11}C]PIB$ production yields and specific activities. $[^{11}C]MeOTf$ was synthesized by using TRACERlab FXC Pro and was transferred into the cartridge by blowing with helium gas for 3 min. To remove byproducts and impurities, cartridges were washed out by 20 mL of 30% EtOH in 0.5 M $NaH_2PO_4$ solution (pH 5.1) and 10 mL of distilled water. And then, $[^{11}C]PIB$ was eluted by 5 mL of 30% EtOH in 0.5 M $NaH_2PO_4$ into the collecting vial containing 10 mL saline. Among the 6 cartridges, only tC18 environmental cartridge could remove impurities and byproducts from $[^{11}C]PIB$ completely and showed higher specific activity than traditional HPLC purification method. This method took only 8 ~ 9 min from methylation to formulation. For the tC18 environmental cartridge and conventional HPLC loop methods, the radiochemical yields were $12.3{\pm}2.2%$ and $13.9{\pm}4.4%$, respectively, and the molar activities were $420.6{\pm}20.4GBq/{\mu}mol$ (n=3) and $78.7{\pm}39.7GBq/{\mu}mol$ (n=41), respectively. We successfully developed a facile on-cartridge methylation method for $[^{11}C]PIB$ synthesis which enabled the procedure more simple and rapid, and showed higher molar radio-activity than HPLC purification method.

반하(Pinellia ternata)가 랫드의 수컷 생식기계에서 3β-HSD,SGP-2 및 AR 유전자 발현에 미치는 영향

연정민, 백인정, 김윤배, 노재섭, 황방연, 김순선, 조대현, 이범준, 윤영원, 남상윤 충북대학교 동물의학연구소 2005 Journal of Biomedical and Translational Research Vol.6 No.2

본문참조

수종의 치면열구 전색재의 전처리가 결합강도에 미치는 영향

민윤경,김신,정태성 大韓小兒齒科學會 1998 大韓小兒齒科學會誌 Vol.25 No.2

For the purpose of comparing the shear bond strengths of pit and fissure sealants, and finding out the more efficient method of tooth surface treatment when the etched surface is contaminaed by saliva or moisture, an experiment was performed on 3 types of pit and fissure sealants. 120 extracted human molars were divided into 3 groups, each of which was composed of 40 specimens sealed with Helioseal. Teethmate-F and FujiⅢ respectively. and each groups was again divided into 4 subgroups according to tooth surface treatment. The shear bond strengths of each froups and subgroup was measured and statistically analyzed. The results obtained were as follows : 1. shear bond strengths of nonfluoridated resin sealant, Helioseal were shown to be higher than those of fluoridated resin sealant. Teethmate-F, but, not significantly different. 2. Shear bond strengths of GI sealant, FujiⅢ were to be markedly lower than those of two resin sealants. 3. When there is moisture contamination, applying primer under sealant (GroupⅣ) results in a significantly stronger bond strength of sealant to enamel than using sealant alone(GroupⅡ) incase of all sealants. 4. When there is no moisture contamination, using primer under sealant(GroupⅢ) results in bond strength equivalent to bond strength on using sealant alone (GroupⅠ). 5. Based on the results above, it was demonstrated that the bond of sealant to tooth surface is greatly affected by saliva contamination and that the complete tooth isolation method should be fully emphasized. The application of primer is recommended when performing sealant under the environment very susceptible to saliva contamination.