佐々木 一郎; 渡辺 茂樹; 大島 康宏; 須郷 由美; 山田 圭一*; 花岡 宏史*; 石岡 典子
Peptide Science 2015, p.243 - 246, 2016/03
Radioisotope labeled peptides with high affinity to receptors overexpressing on the surface of tumor cells are promising for applications in nuclear medicine such as diagnostic radiography and radiotherapy. Radiohalogens such as I and At are useful for clinical imaging and therapeutic applications, and it can be introduced at the position of phenylalanine residue via electrophilic destannylation. KCCYSL (Lys-Cys-Cys-Tyr-Ser-Leu) is a hexapeptide containing disulfide bond. Previous study revealed that KCCYSL has potential as tumor imaging and therapeutic agent targeting tumor cells overexpressing the human epidermal growth factor receptor type 2 (HER2). In this study, we report synthesis and evaluation of radiohalogenated KCCYSL derivatives. Precursor peptides, Boc-F(-SnBu)K(Boc)C(Trt)C(Trt)Y(Bu)S(Bu)L-OH and Boc-F(-SnBu)GS(Bu)GK(Boc)C(Trt)C(Trt)Y(Bu)S(Bu)L-OH, were synthesized by the Fmoc solid phase peptide synthesis. Then, precursor peptides were radioiodinated via electrophilic destannylation, and they were deprotected to obtain F(-I)KCCYSL and F(-I)GSGKCCYSL in radiochemical yield 15% and 17%, respectively. assays of the radioiodinated peptides for HER2 and stability in serum are being undertaken.
森 勝伸*; 佐柄 克哉*; 新井 香織*; 中谷 暢丈*; 大平 慎一*; 戸田 敬*; 板橋 英之*; 小崎 大輔*; 須郷 由美; 渡辺 茂樹; et al.
Journal of Chromatography A, 1431, p.131 - 137, 2016/01
Selective separation and sensitive detection of dissolved silicon and boron (DSi and DB) in aqueous solution was achieved by connecting an electrodialytic ion isolation device (EID), an ion-exclusion chromatography (IEC) column, and a corona charged aerosol detector (CCAD) in sequence. They were separated by IEC using pure water eluent. Detection of DSi and DB by the CCAD was effective for much greater sensitivity than by conductimetric detection. The EID removed salt from the sample prior to the IEC-CCAD. The combination of EID, IEC and CCAD successfully separated and determined DSi and DB in artificial seawater and hot-spring water samples by eluting pure water.
小川 数馬*; 水野 覚瑛*; 鷲山 幸信*; 柴 和弘*; 高橋 成人*; 小阪 孝史*; 渡辺 茂樹; 篠原 厚*; 小谷 明*
Nuclear Medicine and Biology, 42(11), p.875 - 879, 2015/11
Sigma receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide receptor therapy. We have previously synthesized and evaluated I-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[I]pIV], which has a high affinity for sigma receptors. Therefore, (+)-[I]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[At]pAtV, an At-labeled sigma receptor ligand, that has potential use in -radionuclide receptor therapy. The lipophilicity of (+)-[At]pAtV was similar to that of (+)-[I]-pIV. Uptake of DU-145, prostate cancer cell lines, and the biodistribution patterns in DU-145 tumor-bearing mice at 1 h post-injection were also similar between (+)-[At]pAtV and (+)-[I]-pIV. Namely, (+)-[At]pAtV demonstrated high uptake and retention in tumor via binding to sigma receptors.
西中 一朗; 横山 明彦*; 鷲山 幸信*; 前田 英太*; 渡辺 茂樹; 橋本 和幸; 石岡 典子; 牧井 宏之; 豊嶋 厚史; 山田 記大*; et al.
Journal of Radioanalytical and Nuclear Chemistry, 304(3), p.1077 - 1083, 2015/06
29-57MeVのLiビームとPb標的核の反応においてアスタチン同位体Atの生成断面積を線, 線スペクトルメトリーで測定した。生成断面積の励起関数を統計模型モデル計算と比較することで、Li + Pbの反応機構を調べた。44MeVより大きい入射エネルギーでのAtとAtの生成断面積が理論値よりも小さいことから、分解反応が存在することを明らかにした。照射した鉛標的からのアスタチンの化学分離を乾式蒸留法に基づいて調べ、アスタチン製造の相補的な手法を開発した。
花岡 宏史*; 大島 康宏; 鈴木 結利花*; 山口 藍子*; 渡辺 茂樹; 上原 知也*; 永森 收志*; 金井 好克*; 石岡 典子; 対馬 義人*; et al.
Journal of Nuclear Medicine, 56(5), p.791 - 797, 2015/05
Radiolabeled amino acids are superior PET tracers for imaging of malignant tumors, and amino acids labeled with Br, an attractive positron emitter due to its relatively long half-life (t=16.2 h), could potentially be widely usable tumor imaging tracer. In this study, in consideration of stability and tumor specificity, 2-Br-bromo--methyl-L-phenylalanine (2-Br-BAMP) and 4-Br-bromo--methyl-L-phenylalanine (4-Br-BAMP) were designed and their potential as a tumor imaging agent was evaluated. No-carrier-added Br and Br, the latter of which is suitable radiobromine for basic studies due to its longer half-life (t = 57.1 h), were produced. Both Br-BAMPs were stable in the plasma and in the murine body. In biodistribution studies, 2-Br-BAMP showed more rapid blood clearance and lower renal accumulation than did 4-Br-BAMP. More than 90% of injected radioactivity was excreted in the urine by 6 h post-injection of 2-Br-BAMP. High tumor accumulation of 2-Br-BAMP was observed in tumor-bearing mice and PET imaging with 2-Br-BAMP enabled clear visualization of the tumor. These findings suggest that 2-Br-BAMP would constitute a potential new PET tracer for tumor imaging and may eventually enable the wider use of amino acid tracers.
須郷 由美; 佐々木 一郎; 渡辺 茂樹; 大島 康宏; 石岡 典子
JAEA-Review 2014-050, JAEA Takasaki Annual Report 2013, P. 100, 2015/03
MARSGL peptide (H-Met-Ala-Arg-Ser-Gly-Leu-OH) has high affinity to the human epidermal growth factor receptor 2 (HER2) overexpressing in various tumor cells. Copper-64 (Cu) is a useful radionuclide in nuclear medicine, and can be produced by the cyclotron. In this study, we designed and synthesized Cu-labeled MARSGL peptide conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) as a novel positron emission tomography (PET) imaging probe for HER2 overexpressing tumors. The formation of Cu-DOTA-MARSGL was determined by TLC and HPLC compared with a non-radioactive preparation. It was confirmed that Cu-DOTA-MARSGL was obtained in high radiochemical yield more than 94%. We also examined a stability of Cu-DOTA-MARSGL . The chromatogram was not changed after incubation in physiological saline at 37C overnight. In order to evaluate the usefulness as a PET imaging probe, further studies on the stability in human or mice plasma and the cellular uptake are in progress.
佐々木 一郎; 花岡 宏史*; 山田 圭一*; 渡辺 茂樹; 須郷 由美; 大島 康宏; 鈴木 博元; 石岡 典子
Peptide Science 2014, p.257 - 260, 2015/03
We have sought to establish drug discovery system using radioisotope (RI) labeled peptides which have high affinity to target proteins overexpressed in cancers. Of the target proteins, we chose the human epidermal growth factor receptor type 2 (HER2), a membrane protein overexpressed in various cancers to evaluate the drug discovery system. Three series of random hexapeptide libraries introduced a radioiodinated D-tyrosine (y(3-I)) to -terminal were designed and binding assay with HER2-expressed cell lines were conducted in this study. First, we synthesized a series of random hexapeptide libraries with fixed amino acid sequence at 1 and 2 positions, y(3-I)XXXXXX. Non-radioactive random peptide libraries, yXXXXXX, were prepared by Fmoc-SPPS with an automatic peptide synthesizer. Radioiodinated y(3-I)XXXXXX were subsequently synthesized in 30-50% radiochemical yield. Binding assay using HER2-overexpressed cell line showed that high affinity (38-50% dose, n=6) was obtained with yIIXXXX, while other random peptide libraries were yielded low affinity (approximately 1% dose), which indicated that the system using RI labeled random peptide libraries have potential to discover peptide drug for cancer therapy. Preparation of other random hexapeptide libraries are being undertaken.
渡辺 智; 橋本 和幸; 渡辺 茂樹; 飯田 靖彦*; 花岡 宏史*; 遠藤 啓吾*; 石岡 典子
Journal of Radioanalytical and Nuclear Chemistry, 303(1), p.935 - 940, 2015/01
No-carrier-added Lu produced via the Yb(n, ) Yb Lu process was separated from the macroscopic amounts of the Yb target using reversed-phase ion-pair liquid chromatography. To produce a highly purified Lu solution capable of labeling antibodies, the metallic impurities were removed using cation, chelating ion, and anion exchange columns. After the elimination of metallic impurities, the concentrations of Ca, Fe, and Zn were reduced from 87, 340, and 77 ppb to 13, 18, and 9 ppb, respectively. Consequently, the labeling yield of the Lu -labeled antibody increased from less than 5% to 88%.
佐々木 一郎; 山田 圭一*; 渡辺 茂樹; 花岡 宏史*; 須郷 由美; 奥 浩之*; 石岡 典子
JAEA-Review 2013-059, JAEA Takasaki Annual Report 2012, P. 96, 2014/03
Radioisotope (RI)-labeled peptide with high affinity to receptors overexpressing on the surface of tumor cells are promising for applications in nuclear medicine such as diagnostic radiography and radiotherapy. MARSGL (H-Met-Ala-Arg-Ser-Gly-Leu-OH), a linear peptide consisting of six amino acids, has high affinity to HER2/neu receptor overexpressing in various cancer cells. Radiohalogens (radionuclides) such as radioiodine and radiobromine are versatile for clinical imaging and therapeutic applications. Thus, radiohalogenated MARSGL may have potential for clinical applications to HER2 overexpressing tumors. In this study, in order to achieve the labeling of radiohalogen for MARSGL, we design a radioiodinated peptide, F(-I)MARSGL, in which phenylalanine labeled with I (t = 8.0 d) at the position of the aromatic ring is introduced into the N-terminal of MARSGL and report a new technique to prepare radiohalogen of peptide via electrophilic destanylation.
須郷 由美; 佐々木 一郎; 渡辺 茂樹; 大島 康宏; 石岡 典子
Peptide Science 2013, p.355 - 358, 2014/03
HER2 is a member of the epidermal growth factor receptor family, which is overexpressed on the surface of tumor cells. H-Met-Ala-Arg-Ser-Gly-Leu-OH (MARSGL) is a linear peptide having high affinity to HER2 overexpressing in various cancer cells. In the previous study, we have synthesized a novel radioiodinated MARSGL via electrophilic destannylation in high radiochemical yield. Cu is an attractive radionuclide for positron emission tomography imaging as well as radiotherapy due to its half-life of 12.7 h and decay characteristics of both and . 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) is a macrocyclic ligand for various metal ions. In this study, we designed and synthesized Cu-labeled MARSGL peptide conjugated with DOTA as an imaging probe for HER2 overexpressing tumors. In order to evaluate the usefulness of Cu-DOTA-MARSGL peptide as a PET imaging probe, studies were also performed.
Balkin, E. R.*; Hamlin, D. K.*; Gagnon, K.*; Chyan, M.-K.*; Pal, S.*; 渡辺 茂樹; Wilbur, D. S.*
Applied Sciences (Internet), 3(3), p.636 - 655, 2013/09
A "wet chemistry" approach for isolation of At from an irradiated bismuth target is described. The approach involves five steps: (1) dissolution of bismuth target in conc. HNO; (2) removal of the HNO by distillation; (3) dissolution of residue in 8 M HCl; (4) extraction of At from 8 M HCl into DIPE; and (5) extraction of At from DIPE into NaOH. Results from 55 "optimized" At isolation runs gave recovery yields of approximately 78% after decay and attenuation corrections. An attenuation-corrected average of 263 mCi in the target provided isolated (actual) yields of 163 mCi of At. A sixth step, used for purification of At from trace metals, was evaluated in seven runs. In those runs, isolated At was distilled under reductive conditions to provide an average 718% recovery. RadioHPLC analyses of the isolated At solutions, both initial and after distillation, were obtained to examine the At species present. The primary species of At present was astatide, but astatate and unidentified species were also observed. Studies to determine the effect of bismuth attenuation on At were conducted to estimate and attenuation factor (1.33) for adjustment of At readings in the bismuth target.
鈴木 義行*; 山口 充孝; 小高 裕和*; 島田 博文*; 吉田 由香里*; 鳥飼 幸太*; 佐藤 隆博; 荒川 和夫*; 河地 有木; 渡辺 茂樹; et al.
Radiology, 267(3), p.941 - 947, 2013/06
Capabillity tests of 3D imaging for medical applications were performed by using a new Compton camera. F, I and Ga separately compacted into micro tubes were injected subcutaneously into a Wister rat and imaged after sacrifice of the rat (ex-vivo model). In a separate experiment In-chloride and I-Methylnorcholestenol were injected into a rat intravenously and Cu was injected into the stomach orally just before imaging (more physiological model). The Compton camera demonstrated its 3D multinuclear imaging capability by separating out the three nuclear distributions clearly in ex-vivo model. In the more physiological model, the distributions of I and Cu were clearly imaged although In was difficult to visualize due to blurring at low energy region of -ray. In conclusion, our new Compton camera successfully demonstrated highly resolved multiplanar and multinuclear -ray simultaneous imaging.
花岡 宏史*; 渡邉 茂樹; 富永 英之*; 大島 康宏; 渡辺 智; 山田 圭一*; 飯田 靖彦*; 石岡 典子; 遠藤 啓吾*
JAEA-Review 2012-046, JAEA Takasaki Annual Report 2011, P. 89, 2013/01
大島 康宏; 花岡 宏史*; 渡邉 茂樹; 須郷 由美; 渡辺 智; 富永 英之*; 織内 昇*; 遠藤 啓吾*; 石岡 典子
JAEA-Review 2011-043, JAEA Takasaki Annual Report 2010, P. 91, 2012/01
3-[F]Fluoro--methyl-L-tyrosine ([F]FAMT) is a useful amino acid tracer for PET imaging of malignant tumors. FAMT analogs labeled with Br, a positron emitter with a long half-life (t=16.1 h), could be widely used as tracers for tumor imaging. In this study, 3-[Br]bromo--methyl-L-tyrosine ([Br]BAMT) was designed, and its usefulness was evaluated as a novel PET tracer for imaging malignant tumors. In this study, both [Br]BAMT and [Br]BAMT were prepared. [Br]BAMT was stable in vitro, but was catabolized after administration in mice. Cellular accumulation and retention of [Br]BAMT using LS180 colon adenocarcinoma cells were significantly higher than those of [F]FAMT. In biodistribution studies using LS180 tumor-bearing mice, the tumor accumulation of [Br]BAMT was higher than that of [F]FAMT. However, some level of debromination was seen, and this debromination caused more retention of radioactivity in the blood and organs than was seen with [F]FAMT. PET imaging with [Br]BAMT enabled clear visualization of the tumor. In conclusion, although an improvement in stability is still needed, Br-labeled FAMT analogs could potentially serve as PET tracers for the imaging of malignant tumors.
渡辺 智; 渡邉 茂樹; 飯田 靖彦*; 花岡 宏史*; 遠藤 啓吾*; 石岡 典子
JAEA-Review 2011-043, JAEA Takasaki Annual Report 2010, P. 92, 2012/01
現在PET診断に用いられている核種は半減期が2時間以下と非常に短いため、抗体のような集積に時間のかかる化合物を利用したPET診断には限界がある。これを解決するために、本研究では新規ポジトロン放出核種として半減期が16.2時間のBrの製造法の開発を行った。セレン化銅をターゲットとし、Se(p,n) Br反応を用い、原子力機構のTIARA-AVFサイクロトロンからの20MeV, Hビームで照射をしてBrを生成した。Brの回収にはターゲット由来の毒物であるSeの混入を防ぐために乾式蒸留法を採用し、Brトラップ回収条件等の検討により、Brの高純度分離を達成した。分離条件については、回収方法及び電気炉内温度の最適化により、ターゲット中に生成した全Brの放出及びテフロンチューブ内でのロスの低減により、30%程度の回収率を約80%にまで向上させることに成功した。
衛藤 将生*; 神島 吉郎*; 岡村 茂樹*; 渡辺 収*; 大山 一弘*; 根岸 和生; 小竹 庄司*; 阪本 善彦; 上出 英樹
Proceedings of International Conference on Fast Reactors and Related Fuel Cycles (FR 2009) (CD-ROM), 10 Pages, 2012/00
大島 康宏; 花岡 宏史*; 渡邉 茂樹; 須郷 由美; 渡辺 智; 富永 英之*; 織内 昇*; 遠藤 啓吾*; 石岡 典子
Nuclear Medicine and Biology, 38(6), p.857 - 865, 2011/08
3-[F]fluoro--methyl-L-tyrosine ([F]FAMT) is a useful amino acid tracer for positron emission tomography (PET) imaging of malignant tumors. FAMT analogs labeled with Br, a positron emitter with a long half-life (=16.1 h), could be widely used as tracers for tumor imaging. In this study, 3-[Br]bromo--methyl-L-tyrosine ([Br]BAMT) was designed, and its usefulness was evaluated as a novel PET tracer for imaging malignant tumors. In this study, both [Br]BAMT and [Br]BAMT were prepared. [Br]BAMT was stable in vitro, but was catabolized after administration in mice. Cellular accumulation and retention of [Br]BAMT using LS180 colon adenocarcinoma cells were significantly higher than those of [F]FAMT. In biodistribution studies using LS180 tumor-bearing mice, the tumor accumulation of [Br]BAMT was higher than that of [F]FAMT. However, some level of debromination was seen, and this debromination caused more retention of radioactivity in the blood and organs than was seen with [F]FAMT. PET imaging with [Br]BAMT enabled clear visualization of the tumor. In conclusion, although an improvement in stability is still needed, Br-labeled FAMT analogs could potentially serve as PET tracers for the imaging of malignant tumors.
Paudyal, P.*; Paudyal, B.*; 花岡 宏史*; 織内 昇*; 飯田 靖彦*; 吉岡 弘樹*; 富永 英之*; 渡辺 智; 渡邉 茂樹; 石岡 典子; et al.
JAEA-Review 2010-065, JAEA Takasaki Annual Report 2009, P. 108, 2011/01
Non-small cell lung carcinomas (NSCLC) overexpress the Her2/neu gene in approximately 59% of cases. Trastuzumab, a humanized monoclonal antibody, interferes with Her2 signaling and is approved for the treatment of Her2/neu overexpressing breast cancer. However, its therapeutic use in Her2/neu overexpressing NSCLC remains obscure. The present study aimed to determine the role of Cu-labeled trastuzumab positron emission tomography (PET) for non-invasive imaging of Her2/neu expression in NSCLC. Imaging of Her2/neu expression was performed in NCI-H2170 tumor-bearing mice with Cu-DOTA-trastuzumab. PET studies revealed a significantly high accumulation of Cu-DOTA-trastuzumab in the Her2/neu overexpressing NCI-H2170 tumor at 24 h and 48 h post-injection. Cu-DOTA-trastuzumab showed a very clear image of a Her2/neu positive tumor and appeared to be effective as a PET tracer for imaging of Her2/neu gene expression in NSCLC, suggesting its potential clinical use for identifying patients that might benefit from trastuzumab-based therapy.
渡邉 茂樹; 花岡 宏史*; Liang, J. X.*; 飯田 靖彦*; 渡辺 智; 遠藤 啓吾*; 石岡 典子
JAEA-Review 2010-065, JAEA Takasaki Annual Report 2009, P. 107, 2011/01
I--Iodobenzylgunanidine (I-MIBG), functional analogue of norepinephrine, has been employed for the therapy of neuroendcrine tumors which express norepinephrine transporter (NET). I-MIBG scintigraphy has been also used for diagnosis of NET positive tumors such as detecting metastasis, investigating suitability and monitoring response to the treatment with I-MIBG. However, I-MIBG scintigraphy has limitation to diagnose small legions due to its lower sensitivity and spatial resolution. Since positron emission tomography (PET) is superior to scintigraphy, positron emitter labeled MIBG has potential to improve diagnostic ability of NET positive neuroendcrine tumors. Then, we have reveal the utility of positron emitter Br labeled m-bromobenzylguanidine (Br-MBBG) as a PET tracer for NET positive tumor.