アルツハイマー性痴呆の診断を目的とした放射性ヨウ素標識ベサミコールの開発研究

金沢大学アイソトープ総合センター我々はベサミコールがシナプス終末前部のシナプス小胞の膜に存在するアセチルコリントランスポーターに特異的に結合することから、シナプス前コリン作動性神経機能診断薬の開発を目指してベサミコールおよびその類似体の放射性ヨウ素標識化を検討した。まず最初に放射性ヨウ素の導入位置を検討したところベンゼン核のメタ位にヨウ素を導入したm-ヨードベサミコールがベサミコールと同様の性質を保持していることがわかった。そこで次に、光学活性体である放射性ヨウ素標識(-)-m-ヨードベサミコール((-)-mIV)を標識合成し、インビトロおよびインビボ実験を行った結果、(-)-mIVはベサミコールと同じようにアセチルコリントランスポーターに対して光学特異的で高い親和性を示すとともに、他のレセプター(ドーパミン、セロトニン、アドレナリン、アセチルコリンおよびシグマレセプター)に対する親和性が低いことがわかった。またラット脳のオートラジオグラム像も^3H-ベサミコールと一致した。さらに、イボテン酸により右側前脳基底部を破壊することにより作製したアルツハイマー性痴呆モデルラットを用いて、アルツハイマー病の客観的診断薬となりうるか検討した。実験は^I-(-)-mIVおよび^Tc-HMPAOをラットに投与し、イメージングプレートによるダブルトレーサーオートラジオグラフィにより、^I-(-)-mIVの局所脳内分布および局所脳血流分布を比較検討した。その結果、^I-(-)-mIVは大脳皮質の前頭葉、頭頂葉および側頭葉で破壊側が健側に比べ集積が11%減少していた。一方、海馬、線条体、視床および扁桃核群では集積の減少は見られなかった。また脳血流の減少は大脳皮質で若干見られたものの、^I-(-)-mIVの減少率は脳血流に比べ有意に減少していた。このことから、放射性ヨウ素標識(-)-mIVはアルツハイマー病の診断の客観的な指標となりうるシナプス前コリン作動性神経機能診断薬としての可能性が示唆された。The purpose of this investigation is to develop a new presynaptic cholinergic neuron mapping agent. We synthesized levorotatory isomer (-) -m-iodovesamicol ((-) mIV) radioiodinated at the meta position of the 4-phenylpiperidine moiety and evaluated the in vitro and in vivo binding affinity and specificity of [I-125] (-) -mIV for the vesamicol receptor in rat brain, furthermore, evaluated the in vivo characteristics of [I-125] (-) -mIV in the model rat of Alzheimer\u27s disease. In vitro and In vivo binding affinity of [I-125] (-) -mIV for the vesamicol receptor (acetylcholine transporter) was very high and comparable to that of (-) -vesamicol ; the binding affinity for dopamine, serotonin, noradrenaline, acetylcholine and sigma receptors was low. These similar results were derived from saturation binding study ; Kd (18.2nM) and Bmax (660 fmol/mg of protein) of [I-125] (-) -mIV were comparable to those of (-) -vesamicol (Kd=20-30nM,Bmax=334-516fmol/mg of protein). Furthermore, double-tracer autoradiograms using [I-125] (-) -mIV and [Tc-99m] HMPAO in model rat brain of Alzheimer\u27s disease showed a significant 11% decrease of the accumulation of [I-125] (-) -mIV in the projection cortices ipsilateral to the basalforebrain lesion in a unilateral cholinergic denervation model, which is regarded as an experimental model of Alzheimer\u27s disease. The difference between the decrease of the accumulation of [I-125] (-) -mIV (11%) and that of [Tc-99m] HMPAO (4%) in the regions was statistically significant (P<0.01). These results suggest that radioiodinated (-) -mIV may serve as a useful radioligand for mapping presynaptic cholinergic neurons.研究課題/領域番号:08671010, 研究期間(年度):1996 – 1997出典：研究課題「アルツハイマー性痴呆の診断を目的とした放射性ヨウ素標識ベサミコールの開発研究」課題番号08671010（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-08671010/086710101997kenkyu_seika_hokoku_gaiyo/）を加工して作

オピエートレセプターマッピングを目的としたTc-99m標識薬剤の開発に関する研究

金沢大学助手研究課題/領域番号:04770737, 研究期間(年度):1992出典：研究課題「オピエートレセプターマッピングを目的としたTc-99m標識薬剤の開発に関する研究」課題番号04770737（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-04770737/）を加工して作

腫瘍核医学診断のための新しい放射性薬剤の合成開発に関する研究: 非天然型人工アミノ酸類の構造と腫瘍親和性の相関性

取得学位 : 博士（医学）, 学位授与番号 : 医博乙第1129号, 学位授与年月日：平成3年6月5日,学位授与年：199

ドーパミンD_2受容体マッピングを目的としたSPECT用標識薬剤の開発に関する研究

金沢大学アイソトープ総合センターエミッションCTによるD_2レセプターマッピング用の放射性薬剤として、ポジトロン核種で標識したスピペロンやラクロプライドが広く利用・研究されている。しかし、前者はドーパミンD_2レセプター以外にセロトニン5-HT_2レセプターにも高い親和性を有し、後者は内在性の神経伝達物質の影響を受けやすいという欠点がある。今回の研究はスピペロンの窒素部位にベンジル基を導入することにより、ドーパミンD_2レセプターに対してのみ選択的に高い親和性を持つ可能性が高いことから、N-ベンジルスピペロン誘導体類に着目し、そのベンジル部位にヨウ素を導入することによりドーパミンD_2レセプターマッピングのSPECT用放射性薬剤としての可能性を検討した。まず、1-phenyl-1,3,8-triazaspro[4,5]decan-4-oneを出発原料として7行程で目的のN-(2\u27-Iodobenzyl)spiperon(1)とN-(4\u27-Iodobennzyl)spiperon(2)を合成した。合成した2種のIodobenzylapiperon(1,2)のドーパミンD_2およびセロトニン5-HT_2レセプターに対する親和性を薬物阻害実験により調べた結果、1のほうがドーパミンD_2レセプターに対する親和性は保持され、さらにセロトニン5-HT_2レセプターに対する親和性がスピペロンに比べ約1/40と低くなった。次にI-125による標識を硫酸アンモニウムを触媒とする固相交換法により行った。10mugのIodobennzylspiperon(1,2)、5mgの硫酸アンモニウムに37MBqのNa^Iを加え、140℃、25分間反応後、HPLCにより分離することにより、放射化学的収率75%、放射化学的純度97%以上で標識できた。今後、I-125で標識した1を用いて、ラット使った動物実験を行い、脳-血液関門の透過性、ドーパミンD_2レセプターの結合の選択性を調べ、インビボにおける有用性について検討を行う予定である。研究課題/領域番号:05770667, 研究期間(年度):1993出典：研究課題「ドーパミンD_2受容体マッピングを目的としたSPECT用標識薬剤の開発に関する研究」課題番号05770667（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-05770667/）を加工して作

Rapid reduction of sigma(1)-Receptor binding and F-18-FDG uptake in rat gliomas after in vivo treatment with doxorubicin

sigma-Receptors are strongly overexpressed in most rodent and human tumors and are proliferation markers. To evaluate the potential of a radiolabeled sigma(1)-ligand for therapy monitoring, we compared early changes of C-11-1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine (C-11-SA4503) binding and F-18-FDG uptake in gliomas after in vivo chemotherapy. Methods: C6 cells (2.5 x 10(6)) were subcutaneously injected into the right shoulder of male Wistar rats. After 7 cl, the tumor volume was 0.60 +/- 0.08 cm(3). Animals then received either saline or doxorubicin (8 mg/kg, intraperitoneally). One control and 1 treated rat were imaged simultaneously, 24 or 48 h after treatment, under pentobarbital anesthesia. Rodents (n = 20) were scanned first with C-11-SA4503 (25 MBq, intravenously) followed more than 100 min afterward by 18F-FDG (20 MBq, intravenously), using a dedicated small-animal PET camera (60-min protocol, tumors in the field of view). Tumor homogenates were prepared and subjected to sigma-receptor assays. The biodistribution of 18F-FDG was assessed. Results: Tumors appeared 4-5 d after inoculation and grew exponentially. No significant reduction of tumor growth was visible within 48 h after doxorubicin treatment. Both PET tracers visualized the tumors and showed reduced uptake after chemotherapy (C-11-SA4503: 26.5% +/- 6.5% at 24 h, 26.5% +/- 7.5% at 48 h; 18F-FDG: 22.6% +/- 3.2% at 24 h, 27.4% +/- 3.2% at 48 h; ex vivo F-18-FDG: 22.4% +/- 5.4% at 24 h, 31.7% +/- 12.7% at 48 h). sigma(1)-Receptor density in treated tumors was also reduced (from 172 +/- 35 to 125 +/- 28 fmol/mg of protein). Conclusion: Both C-11-SA4503 binding and 18F-FDG uptake declined in gliomas after chemotherapy. Decreased binding of C-11-SA4503 corresponded to a loss of (sigma(1)-receptors from the tumors. Changes in tracer uptake preceded the morphologic changes by at least 48 h

In Vivo and in Vitro Characteristics of Radiolabeled Vesamicol Analogs as the Vesicular Acetylcholine Transporter Imaging Agents

金沢大学疾患モデル総合研究センターThe vesicular acetylcholine transporter (VAChT), a presynaptic cholinergic neuron marker, is a potential internal molecular target for the development of an imaging agent for early diagnosis of neurodegenerative disorders with cognitive decline such as Alzheimer\u27s disease (AD). Since vesamicol has been reported to bind to VAChT with high affinity, many vesamicol analogs have been studied as VAChT imaging agents for the diagnosis of cholinergic neurodeficit disorder. However, because many vesamicol analogs, as well as vesamicol, bound to sigma receptors (σ1 and σ2) besides VAChT, almost all the vesamicol analogs have been shown to be unsuitable for clinical trials. In this report, the relationships between the chemical structure and the biological characteristics of these developed vesamicol analogs were investigated, especially the in vitro binding profile and the in vivo regional brain accumulation. © 2018 Kazuma Ogawa and Kazuhiro Shiba

Evaluation of Chlorella as a Decorporation Agent to Enhance the Elimination of Radioactive Strontium from Body

Background Release of radionuclides, such as 137Cs and 90Sr, into the atmosphere and the ocean presents an important problem because internal exposure to 137Cs and 90Sr could be very harmful to humans. Chlorella has been reported to be effective in enhancing the excretion of heavy metals; thus, we hypothesized that Chlorella could also enhance the elimination of 137Cs or 90Sr from the body. We evaluated the potential of Chlorella as a decorporation agent in vitro and in vivo, using 85Sr instead of 90Sr. Methods In vitro experiments of adsorption of 137Cs and 85Sr to Chlorella were performed under wide pH conditions. The maximum sorption capacity of Chlorella to strontium was estimated using the Langmuir model. A 85Sr solution was orally administrated to mice pretreated with Chlorella. At 48 h after 85Sr administration, the biodistribution of radioactivity was determined. Results In the in vitro experiments, although 85Sr barely adsorbed to Chlorella at low pH, the 85Sr adsorption ratio to Chlorella increased with increasing pH. The maximum sorption capacity of Chlorella to strontium was 9.06 mg / g. 137Cs barely adsorbed to Chlorella under any pH conditions. In the biodistribution experiments, bone accumulation of radioactivity after 85Sr administration was significantly decreased in the Chlorella pretreatment group compared with the non-treatment control group. Conclusions In conclusion, these results indicated that Chlorella could inhibit the absorption of 90Sr into the blood and enhance the elimination of 90Sr from the body through adsorption in intestine. Further studies are required to elucidate the mechanism and the components of Chlorella needed for adsorption to strontium and could promote the development of more effective decorporation agents. © 2016 Ogawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Liver-specific γ-glutamyl carboxylase-deficient mice display bleeding diathesis and short life span

Liver-Specific γ-Glutamyl Carboxylase-Deficient Mice Display Bleeding Diathesis and Short Life Span. Azuma K, Tsukui T, Ikeda K, Shiba S, Nakagawa K, et al. PLOS ONE. 2014. 9(2) doi:10.1371/journal.pone.008864

Preparation and evaluation of a radiogallium complex-conjugated bisphosphonate as a bone scintigraphy agent

金沢大学医薬保健研究域薬学系Introduction: 68Ga is a radionuclide of great interest as a positron emitter for positron emission tomography (PET). To develop a new bone-imaging agent with radiogallium, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as a chelating site and Ga-DOTA complex-conjugated bisphosphonate, which has a high affinity for bone, was prepared and evaluated. Although we are interested in developing 68Ga-labeled bone imaging agents for PET, in these initial studies 67Ga was used because of its longer half-life. Methods: DOTA-conjugated bisphosphonate (DOTA-Bn-SCN-HBP) was synthesized by conjugation of 2-(4-isothiocyanatebenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate). 67Ga-DOTA-Bn-SCN-HBP was prepared by coordination with 67Ga, and its in vitro and in vivo evaluations were performed. Results: 67Ga-DOTA-Bn-SCN-HBP was prepared with a radiochemical purity of over 95% without purification. 67Ga-DOTA-Bn-SCN-HBP had great affinity for hydroxyapatite in binding assay. In biodistribution experiments, 67Ga-DOTA-Bn-SCN-HBP accumulated in bone rapidly but was hardly observed in tissues other than bone. Pretreatment of an excess amount of alendronate inhibited the bone accumulation of 67Ga-DOTA-Bn-SCN-HBP. Conclusions: 67Ga-DOTA-Bn-SCN-HBP showed ideal biodistribution characteristics as a bone-imaging agent. These findings should provide useful information on the drug design of bone imaging agents for PET with 68Ga. © 2010 Elsevier Inc. All rights reserved