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佐々木 一郎; 山田 圭一*; 渡邉 茂樹; 花岡 宏史*; 須郷 由美; 奥 浩之*; 石岡 典子
Peptide Science 2013, p.157 - 160, 2013/03
Radioisotope (RI)-labeled peptides which have the high affinity to receptors on surface of the tumor cell are promising for diagnostic radiography (PET and SPECT) and radiotherapy. MARSGL (H-Met
-Ala
-Arg
-Ser
-Gly
-Leu
-OH), a linear hexapeptide consisting of six amino acids, has the high affinity to HER2/neu receptor overexpressing in various cancer cells. Thus, radiolabeled MARSGL has potential for the above mentioned purposes. Radiohalogens have various useful radionuclides, which could be introduced to aromatic compounds via tin-halogen exchange reaction. In this study, stannylated peptide Boc-F(
-SnBu
)MAR(Pbf)S(
Bu)GL-OH was synthesized to prepare radiohalogen (
Br or 
I)-labeled FMARSGL derivatives. First, Boc-Phe(-SnBu)-OH was prepared from Boc-Phe(-I)-OMe via Pd(0)-catalyzed coupling reaction with (BuSn)
and was successfully introduced into 
-terminal of H-MARSGL-Trt(2-Cl) resin synthesized from H-Leu-Trt(2-Cl) resin by Fmoc-SPPS. After cleavage reaction of Boc-F(-SnBu)MAR(Pbf)S(Bu)GL-Trt(2-Cl) resin with 25% 1,1,1,3,3,3-hexafluoro-2-propanol in CHCl, Boc-F(-SnBu)MAR(Pbf)S(Bu)GL-OH was obtained and identified by using ESI-MS and NMR. Synthesis of I-labeled FMARSGL is due to report in this presentation.
I]-sansalvamide A derivative渡邉 茂樹; 山田 圭一*; 津久井 匠隆*; 花岡 宏史*; 大島 康宏; 山口 藍子*; 奥 浩之*; 石岡 典子
JAEA-Review 2012-046, JAEA Takasaki Annual Report 2011, P. 88, 2013/01
Sansalvamide A (SA), a penta cyclic peptide isolated marine fungus, is a lead compound of anti-cancer reagent because the peptide has cytotoxicity against various cancer cell lines. Halogenated SA derivatives (SA-X, X = Cl, Br, I) was prepared and remarkable cytotocity against malignant human breast cancer. In this study, a radiohalogenated SA derivative [I]SA-I was prepared to conduct in vivo evaluation of SA derivatives. Synthetic scheme of [I]SA-I are as follows: an iodinated linear peptide, Boc-F(p-I)LLVL-OMe, was prepared by the conventional solid phase peptide synthesis. After preparation of stannylated peptide, Boc-F(p-SnBu)LLVL-OMe, I was labeled with electrophilic destannylation in the presence of oxidizing reagent. After deprotection of N- and C-termius, [I]SA-I was obtained successfully by macrocyclization in liquid phase. Overall labeled yield was 7%. To our best knowledge, this report is the first on the synthesis of radiolabeled SA derivative. In vivo evaluation of the SA derivative using [I]SA-I is being undertaken.
Br-labeled amino acid derivative for PET imaging of tumor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
近年、がんに対する特異性が高いPET薬剤として、
Cや
Fで標識したアミノ酸誘導体が開発され、臨床応用されるようになってきた。しかしながらCやFは半減期が非常に短いため、それぞれの病院で製造・合成する必要があり、限られた施設でしか使えないのが現状である。一方、Brは、半減期が16.1時間とポジトロン放出核種としては比較的長く、またハロゲン核種であるため母体化合物との結合にキレート剤等が必要ないことから、アミノ酸のような低分子化合物に対しても応用可能である。そこで本研究では、広く臨床使用することが可能な、新規がん診断用PETイメージング薬剤としてBr標識アミノ酸誘導体の開発を計画した。基礎検討には半減期が長い放射性臭素である
Br(半減期57時間)を用いて行うこととした。Br標識アミノ酸としては、
メチルフェニルアラニン(-Me-Phe)のパラ位にBrを導入したBr--Me-Pheを設計した。Br--Me-Pheは標識率25-40%で合成することができた。Br--Me-Pheを担癌マウスに投与したところ、腫瘍への高い集積性を示し、投与3時間後の腫瘍対血液比は3.94、腫瘍対筋肉比は3.95であった。Br--Me-Pheを担癌マウスに投与してPET撮像を行ったところ、腫瘍を明瞭に描出することができた。以上の結果から、Br--Me-Pheの新規がんイメージング薬剤としての有用性が示唆された。
Br]bromo--methyl-L-tyrosine, a novel tyrosine analog for PET imaging of tumors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.
Br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。
渡邉 茂樹; 石岡 典子
放射化学ニュース, (24), p.40 - 45, 2011/08
放射化学ニュースにおける「放射化学の最前線; マリーキュリーが目指したテーマ」の特集において「アイソトープの医学利用」と題して投稿する。本投稿内容は、医学分野におけるRIの利用についての現状、及び、これまでRI医療応用研究グループで進めてきた加速器あるいは原子炉を用いた新しいRIである
Cu, Br, 
Luの製造とこれらRIを標識した薬剤の開発に関する最新成果について紹介したものである。
Br]bromo--methyl-L-tyrosine, a novel tyrosine analog for positron emission tomography imaging of tumors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
被引用回数：14 パーセンタイル：47.34(Radiology, Nuclear Medicine & Medical Imaging)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.
Br-MBBG石岡 典子; 渡邉 茂樹; 花岡 宏史*
内分泌画像検査・診断マニュアル, p.218 - 219, 2011/04
「内分泌画像検査・診断マニュアル」は、画像検査に関する実践的なマニュアルとして、内分泌系の系統別,疾患別に画像検査の目的,前処置,実施方法,結果の評価,副作用と対処法などをコンパクトにまとめかつ可能な限り多くの画像を掲載し、内分泌代謝疾患の診療に従事するすべての医師を対象として、いずれの施設でもこれまで以上に内分泌疾患の診断が円滑に実施できることを最大の目的として出版される。第8章「新しい画像検査」において、RI医療応用研究グループで開発した内分泌疾患のPET検査を可能にする新しいRI薬剤、Br-MBBGについて、臨床医のためのポイントも含め解説する。
渡邉 茂樹; 石岡 典子
放射線と産業, (129), p.27 - 31, 2011/03
「イオンビームを用いたバイオ・医療への応用研究の最前線」の特集において「がん診断・治療に向けた新しいRI標識薬剤の開発」と題して投稿する。本投稿内容は、これまでRI医療応用研究グループで進めてきた加速器又は原子炉を用いた新しいRIの製造法、及びこれらRIの標識薬剤の開発に関する最新成果について記述するものである。具体的には加速器を用いて製造したCu及びBr、原子炉を用いて製造したLuのそれぞれの製造法,標識薬剤合成、及びPET診断用薬剤(Cu, Br)又は治療用薬剤(Lu)としての評価に関する最新の研究内容を紹介する。
Cu -labeled trastuzumab PETPaudyal, 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.
Br-
-bromobenzylguanidine (Br-MBBG)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.
Br-MBBGを用いた褐色細胞腫のPETイメージング渡邉 茂樹; 石岡 典子
Isotope News, (680), p.2 - 6, 2010/12
RI・放射線に関する新研究について、その現状と将来の展望を紹介する「展望」において、Br-MBBGを用いた褐色細胞腫のPETイメージングと題して投稿する。本投稿内容は、これまで進めてきたBr標識MBBGの開発とPETイメージングへの応用について記述するものである。具体的にはBr標識MBBGの合成と、褐色細胞腫細胞移植モデルマウスを用いた体内分布実験及びPET実験の結果について紹介し、MBBGのPET用薬剤としての有用性について議論した。
Br-
-bromobenzylguanidine渡邉 茂樹; 花岡 宏史*; Liang, J. X.; 飯田 靖彦*; 遠藤 啓吾*; 石岡 典子
Journal of Nuclear Medicine, 51(9), p.1472 - 1479, 2010/09
被引用回数：21 パーセンタイル：56.8(Radiology, Nuclear Medicine & Medical Imaging)
-iodobenzylguanidine (MIBG) labeled has been widely used for the diagnosis and radiotherapy of norepinephrine transporter (NET)-expressing tumors. This study demonstrated that a positron emitter Br labeled -bromobenzylguanidine (Br-MBBG) was prepared and evaluated as a potential PET tracer for imaging NET-expressing tumors. Br-MBBG was stable in vitro, but some time-dependent dehalogenation was observed after administration in normal mice. MBBG showed high uptake in PC-12 tumor cells, and this uptake was significantly decreased by the addition of NET inhibitors. In biodistribution, MBBG showed high tumor accumulation (32.0 
18.6% ID/g at 3 h p.i.) and the tumor-to-blood ratio reached as high as 54.4 31.9. Tumor uptake of MBBG correlated very well with that of I-MIBG (r = 0.997), but not with F-FDG. MBBG-PET showed a very clear image of the transplanted tumor with high sensitivity, and the visualized lesion was different from that by FDG-PET. These results indicated that Br-MBBG would be a potential PET tracer for imaging NET-expressing neuroendocrine tumors, and could provide useful information for determining the indications for I-MIBG therapy.
坂中 章悟*; 明本 光生*; 青戸 智浩*; 荒川 大*; 浅岡 聖二*; 榎本 収志*; 福田 茂樹*; 古川 和朗*; 古屋 貴章*; 芳賀 開一*; et al.
Proceedings of 1st International Particle Accelerator Conference (IPAC '10) (Internet), p.2338 - 2340, 2010/05
日本においてERL型放射光源を共同研究チームで提案している。電子銃,超伝導加速空洞などの要素技術開発を進めている。また、ERL技術の実証のためのコンパクトERLの建設も進めている。これら日本におけるERL技術開発の現状について報告する。
Cu-labeled trastuzumab PETPaudyal, 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.
Cancer Science, 101(4), p.1045 - 1050, 2010/04
被引用回数：38 パーセンタイル：66.53(Oncology)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.
渡辺 智; 橋本 和幸; 渡邉 茂樹; 飯田 靖彦*; 花岡 宏史*; 遠藤 啓吾*; 石岡 典子
JAEA-Review 2009-041, JAEA Takasaki Annual Report 2008, P. 109, 2009/12
われわれは、がんに特異的に濃集するLu-抗体を開発し、がん治療薬としての有用性を評価することを目指している。そのためには、高純度で無担体のLuが必要である。そこで、本研究では、Lu-抗体の合成が可能な無担体Luの製造法の開発を行った。濃縮
YbOターゲットを原子炉JRR-3で照射し、Yb(n, 
) Yb(半減期1.91時間)
Lu反応でLuを作製した。照射済みの濃縮YbOを塩酸で溶解し、逆相シリカゲルカラムにチャージし、あらかじめ不純物元素を取り除くために陽イオン交換カラム及びキレート交換カラムで精製した0.25M 2-ヒドロキシイソ酪酸(2-HIBA)/0.1M 1-オクタンスルホン酸ナトリウム(1-OS)を溶離液として用い、LuとターゲットであるYbとを分離した。分離後のLuフラクションを陽イオン交換カラムに通して2-HIBA/1-OSを完全に除去し、さらに残った不純物元素を取り除くために陰イオン交換カラムを通して最終Lu溶液を得た。このLuを用いてLu-抗体の標識実験を行った結果、標識率は80%以上であることがわかり、抗体への標識が可能な高純度無担体Luの製造が可能となった。
飯田 靖彦*; 花岡 宏史*; 渡辺 智; 渡邉 茂樹; 石岡 典子; 吉岡 弘樹*; 山元 進司*; Paudyal, P.*; Paudyal, B.*; 樋口 哲也*; et al.
JAEA-Review 2009-041, JAEA Takasaki Annual Report 2008, P. 108, 2009/12
As antibody binds specifically to corresponding antigens, radiolabeled antibody also binds to cells expressing antigens on surface membranes. Large amounts of antibodies labeled with cytotoxic radionuclides are administered intravenously in cancer patients, after diagnostic imaging using the tracer amount of radiolabeled antibody. In this study, we developed this therapy, called radioimmunotherapy, for effective treatment in cancer patients without damaging normal cells which do not express antigens. We developed Lu-DOTA-NuB2 using carrier-free Lu, and obtained remarkable results for decreasing tumor. Tumor specific radionuclide therapy using Lu is effective therapy with less adverse reactions.
Br-m-bromobenzylguanidine (Br-MBBG) for in vivo imaging of neuroendcrine-tumor with PET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 2009-041, JAEA Takasaki Annual Report 2008, P. 107, 2009/12
I-m-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 the neuroendcrine tumors. However, MIBG scintigraphy has been not enough for diagnosis of neuroendcrine tumors due to poor sensitivity and resolution. Positron emission tomography (PET) is superior to spatial resolution and quantitative capability. To improve diagnostic ability of NET positive neuroendcrine tumor, positron emitter Br labeled m-bromobenzylguanidine (Br-MBBG) was synthesized. Br was synthesized successfully with 50% of labeling efficiency, and the compound had great stability in vitro. In biodistribution studies using neuroendcrine tumor xenografted nude mice, Br-MBBG showed highest accumulation to the tumor, which is relative high compared to that of MIBG. These results indicate that Br-MBBG is useful for in vivo imaging of neuroendcrine tumors with PET.
Cu渡邉 茂樹; 渡辺 智; Liang, J. X.; 花岡 宏史*; 遠藤 啓吾*; 石岡 典子
Nuclear Medicine and Biology, 36(6), p.587 - 590, 2009/09
被引用回数：6 パーセンタイル：22.73(Radiology, Nuclear Medicine & Medical Imaging)We have developed a production method for no-carrier-added copper-64 (Cu) by using chelating resin bearing iminodiacetic acid groups. We optimized the condition for selective separation of radioactive copper by using chelating resin from nickel and cobalt. Radioactive copper was separated completely using 0.1 M and 2 M HCl solution. In production of no-carrier-added Cu, the average 87% of Cu was isolated from the NiO target with high radionuclide purity (
99%). In order to investigate the quality of the obtained Cu, metallic impurities contained in the Cu solution were analyzed by means of inductive coupled-plasma mass spectroscopy (ICP-MS) and optical emission spectroscopy (ICP-OES). It was observed that extremely low amounts of metal ion were contained in the Cu. The Cu solution showed high specific activity (average: 594.7 GBq/
mol). In this study, the chelating exchange method yielded high-quality of Cu sufficient for the synthesis of Cu-labeled radiopharmaceuticals and medical applications.
Cu-labeled DOTA-
-Phe-Tyr-octreotide (Cu-DOTA-TOC) for imaging somatostatin receptor-expressing tumors花岡 宏史*; 富永 英之*; 山田 圭一*; Paudyal, P.*; 飯田 靖彦*; 渡邉 茂樹; Paudyal, B.*; 樋口 徹也*; 織内 昇*; 遠藤 啓吾*
Annals of Nuclear Medicine, 23(6), p.559 - 567, 2009/08
被引用回数：17 パーセンタイル：46.65(Radiology, Nuclear Medicine & Medical Imaging)In-111 (
In)-labeled octreotide has been clinically used for imaging somatostatin receptor-positive tumors, and radiolabeled octreotide analogs for positron emission tomography (PET) have been developed. The aim of this study is to produce and fundamentally examine a Cu-labeled octreotide analog, Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid--Phe-Tyr-octreotide (Cu-DOTA-TOC). Cu-DOTA-TOC can be produced in amounts efficient for clinical study with high radiochemical yield. Cu-DOTA-TOC was stable in vitro, but time-dependent transchelation to protein was observed after injection into mice. In biodistribution studies, the radioactivity of Cu was higher than that of In in all organs except kidney. In tumor-bearing mice, Cu-DOTA-TOC showed a high accumulation in the tumors, and the tumor-to-blood ratio reached as high as 8.81 1.17 at 6 h after administration. Cu-DOTA-TOC showed significantly higher accumulation in the tumor than Cu-TETA-OC and Cu-DOTA-OC. PET showed a very clear image of the tumor, which was comparable to that of F-FDG PET and very similar to that of Cu-TETA-OC. Cu-DOTA-TOC clearly imaged a somatostatin receptor-positive tumor and seemed to be a potential PET tracer in the clinical phase.
