壊変系列を伴うα線放出核種の化学的変化に対応できるビオチン誘導キレート薬剤の開発

金沢大学医薬保健研究域医学系本研究ではα線放出核種を対象として、これらの核種を治療に使用するために必要な二官能性キレート薬剤を開発することを目的としてきた。そのための基礎的な条件としてキレート剤の選定、およびキレートと結合した放射性核種が壊変後においても結合を維持できるかといった項目を検討してきた。この検討の際に、骨へ集積しやすいラジウム(Ra)やトリウム(Th)、特にアクチニウム系列核種^Th(T_=18.72d)と骨親和性のキレート剤であるEDTMPとの錯体を合成し、動物実験の結果から^Thの選択的骨集積および娘核種^Ra(T_=11.435d)の高い骨内保持を確認した(昨年度の報告)。本実験ではさらに^Ra以降の娘核種^Pb(T_=36.1m)の骨内保持に関して検討を行った。Raの持つ高い骨集積性と娘核種の骨内保持に影響を与える因子を確認するために^Raと同じ壊変様式を示すトリウム系列核種^Ra(T_=3.66d)を用い、それぞれの娘核種^Pb,^Pbの骨内保持率を比較検討した。Raは骨に対し特異的に集積し、^Ra同位体間の集積の違いは見られなかった。投与後初期から経時的に軟組織からのRaの早いクリアランスが観測されたが、骨での取り込み率は一定であった。^Pbは^Ra投与後の経過時間が長期化(3時間後:68.4%,2日後:77.4%,7日後:85.3%)するほど^Pbの骨内保持率は上昇した。これに対し^Pbは^Ra投与後2日で39.1%であった。Pb元素の持つ骨親和性や、系列中のPo同位体の半減期が非常に短いことなどから、Pbの骨内保持には希ガス元素のRnの半減期が重要であることが確認された。特に^Pbの場合、親核種の^Rnの半減期が短い(T_=3.96秒)ことが骨からの遊離を少なくしていると考えられる。さらにPb保持率の時間依存性が見られたことからRaの骨内への内在化が示唆された。この結果は^Th-EDTMPを転移性骨腫瘍治療に用いる際に、^Ra以下の娘核種が高い割合で長期間骨に保持され、その結果高い線量を腫瘍に対して照射できる可能性を支持している。研究課題/領域番号:14770448, 研究期間(年度):2002 – 2004出典：「壊変系列を伴うα線放出核種の化学的変化に対応できるビオチン誘導キレート薬剤の開発」研究成果報告書　課題番号14770448（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-14770448/)を加工して作

非平衡型複数α線放出インビボジェネレーターを利用した転移性骨腫瘍治療法の開発

金沢大学医薬保健研究域医学系これまでに転移性骨腫瘍治療の際に副作用(特に骨髄毒性)を起こさない投与量(最大耐用線量)を決定(^Th-EDTMP:250kBq/kg)した。今年度はさらにα線放出薬剤^Th-EDTMPによる転移性骨腫瘍の治療効果を検証するために、1)骨転移モデルラットを作製し、擬似的に作成した骨転移がどのようにして形成されるかを経時的に観察し、2)α線による疼痛緩和および抗腫瘍効果について検討した。雌性Sprague-Dawley(SD)ラットの左足膝関節から足方1cm遠方の部位に同系乳癌細胞MRMT-1(3×10^3個/3μL)を移植した骨転移モデルラット作製し、骨転移形成の形態画像及び機能画像による経時的評価の検討をした。作製2週間後には全てのラットにおいて単純X線写真上の溶骨化および骨診断用放射性医薬品の集積による骨転移形成が確認された。次にモデルラット作製2週間後に^Th-EDTMPを尾静脈投与し、von Frey filament test及び腫瘍体積測定による治療効果、体重測定及び血球数測定による骨髄毒性を検討した。比較対象にはRI非投与群を作製した。結果として^Th-EDTMPによる骨髄毒性は表れなかったが、治療効果があったと判定するのは困難であった。von Frey filament testによりα線による疼痛緩和を確認できたが、腫瘍体積は^Th-EDTMP投与群および非投与群共に増加した。骨腫瘍が骨髄内から骨外へ浸潤した場合、α線で治療を行うことは、α線の飛程と腫瘍サイズの問題から困難であると考えられる。骨転移が形成に於いて、より早期の段階での治療がα線を用いる場合には有用であることが考えられる。今後さらに骨転移の状態や転移癌の種類を変化させながらの詳細な検討をする必要性がある。研究課題/領域番号:18790881, 研究期間(年度):2006 – 2007出典：「非平衡型複数α線放出インビボジェネレーターを利用した転移性骨腫瘍治療法の開発」研究成果報告書　課題番号18790881（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-18790881/)を加工して作

227Th-EDTMP: 転移性骨腫瘍治療の可能性を持つ薬剤

取得学位 : 博士（保健学）, 学位授与番号 : 医博甲第1701号, 学位授与年月日 : 平成17年3月22日, 学位授与大学 : 金沢大学, 主査 : 天野 良平, 副査 :高山 輝彦, 川井 惠

227Th-EDTMP: A potential therapeutic agent for bone metastasis

金沢大学大学院医学系研究科保健学専攻The biodistribution of 227Th-EDTMP and retention of its daughter nuclide 223Ra were examined. 227Th-EDTMP was found to show high uptake and long-term retention in bone. The clearance of 227Th-EDTMP from blood and soft tissues was rapid and the femur-to-tissue uptake ratios reached more than 100 within 30 min for all tissues except the kidney. Seven and 14 days after injection of 227Th-EDTMP, the retention index of 223Ra in bone showed high values, and the differences between these time points were not significant. Therefore, 227Th-EDTMP is a potential radiotherapeutic agent for bone metastasis

Evaluation of radioiodinated vesamicol analogs for sigma receptor imaging in tumor and radionuclide receptor therapy

金沢大学医薬保健研究域薬学系It has been reported that sigma receptors are highly expressed in a variety of human tumors. In this study, we selected (+)-2-[4-(4-iodophenyl)piperidino] cyclohexanol [(+)-pIV] as a sigma receptor ligand and evaluated the potential of radioiodinated (+)-pIV for tumor imaging and therapy. (+)-[125/131I]pIV was prepared by an iododestannylation reaction under no-carrier-added conditions with radiochemical purity over 99% after HPLC purification. Biodistribution experiments were performed by the intravenous injection of (+)-[125I]pIV into mice bearing human prostate tumors (DU-145). Blocking studies were performed by intravenous injection of (+)-[125I]pIV mixed with an excess amount of unlabeled sigma ligand into DU-145 tumor-bearing mice. For therapeutic study, (+)-[131I]pIV was injected at a dose of 7.4 MBq followed by measurement of the tumor size. In biodistribution experiments, (+)-[125I]pIV showed high uptake and long residence in the tumor. High tumor to blood and muscle ratios were achieved because the radioactivity levels of blood and muscle were low. However, the accumulations of radioactivity in non-target tissues, such as liver and kidney, were high. The radioactivity in the non-target tissues slowly decreased over time. Co-injection of (+)-[125I]pIV with an excess amount of unlabeled sigma ligand resulted in a significant decrease in the tumor/blood ratio, indicating sigma receptor-mediated tumor uptake. In therapeutic study, tumor growth in mice treated with (+)-[131I]pIV was significantly inhibited compared to that of an untreated group. These results indicate that radioiodinated (+)-pIV has a high potential for sigma receptor imaging in tumor and radionuclide receptor therapy. (Cancer Sci 2009). © 2009 Japanese Cancer Association

Thallium transport and the evaluation of olfactory nerve connectivity between the nasal cavity and olfactory bulb

金沢大学医学部附属病院耳鼻咽喉科Little is known regarding how alkali metal ions are transported in the olfactory nerve following their intranasal administration. In this study, we show that an alkali metal ion, thallium is transported in the olfactory nerve fibers to the olfactory bulb in mice. The olfactory nerve fibers of mice were transected on both sides of the body under anesthesia. A double tracer solution (thallium-201, 201Tl; manganese-54, 54Mn) was administered into the nasal cavity the following day. Radioactivity in the olfactory bulb and nasal turbinate was analyzed with gamma spectrometry. Auto radiographic images were obtained from coronal slices of frozen heads of mice administered with 201Tl or 54Mn. The transection of the olfactory nerve fibers was confirmed with a neuronal tracer. The transport of intranasal administered 201Tl/54Mn to the olfactory bulb was significantly reduced by the transection of olfactory nerve fibers. The olfactory nerve transection also significantly inhibited the accumulation of fluoro-ruby in the olfactory bulb. Findings indicate that thallium is transported by the olfactory nerve fibers to the olfactory bulb in mice. The assessment of thallium transport following head injury may provide a new diagnostic method for the evaluation of olfactory nerve injury. © The Author 2007. Published by Oxford University Press. All rights reserved

Reduction of 223Ra retention in the Large Intestine During Targeted Alpha Therapy with 223RaCl2 by Oral BaSO4 Administration in Mice

Background: Targeted alpha therapy with 223RaCl2 is used to treat skeletal metastases of hormone-refractory prostate cancer. The intravenous injection of 223RaCl2 causes gastrointestinal disorders such as nausea, abdominal discomfort, and diarrhea as frequent clinical adverse events caused by radiation. BaSO4 is known to display Ra2+ ion uptake in its structure and is clinically used as a contrast agent for X-ray imaging following oral administration. Here, we investigated the feasibility of a method to reduce 223Ra retention in the large intestine with BaSO4 by biodistribution studies in mice. Methods: 223RaCl2 biodistribution was examined in ddY mice after intravenous administration (10 kBq/mouse).BaSO4 (100 mg/mouse) was orally administered 1 h before 223RaCl2 injection. We also investigated the effect of laxative treatment on BaSO4 activity, since laxatives are clinically used with BaSO4 to avoid impaction in the large intestine. Results: BaSO4 significantly reduced 223Ra retention in the large intestine after 223RaCl2 injection in mice when compared with the control without BaSO4 administration (P < 0.05). Excretion of 223Ra into the feces was significantly increased by BaSO4 administration (P < 0.05). Laxative treatment did not affect BaSO4 activity in reducing 223Ra retention, although no additional effect of laxative treatment to 223Ra excretion was observed in mice. Conclusions. BaSO4 administration was effective in reducing 223Ra retention in the large intestine during 223RaCl2 therapy, and laxative treatment did not attenuate BaSO4 activity. This method could be useful in reducing adverse events caused by radiation exposure to the large intestine during 223RaCl2 therapy

Assessment of Olfactory Nerve by SPECT-MRI Image with Nasal Thallium-201 Administration in Patients with Olfactory Impairments in Comparison to Healthy Volunteers

Purpose: The aim of this study was to assess whether migration of thallium-201 (201Tl) to the olfactory bulb were reduced in patients with olfactory impairments in comparison to healthy volunteers after nasal administration of 201Tl. Procedures: 10 healthy volunteers and 21 patients enrolled in the study (19 males and 12 females; 26-71 years old). The causes of olfactory dysfunction in the patients were head trauma (n = 7), upper respiratory tract infection (n = 7), and chronic rhinosinusitis (n = 7). 201TlCl was administered unilaterally to the olfactory cleft, and SPECT-CT was conducted 24 h later. Separate MRI images were merged with the SPECT images. 201Tl olfactory migration was also correlated with the volume of the olfactory bulb determined from MRI images, as well as with odor recognition thresholds measured by using T&T olfactometry. Results: Nasal201Tl migration to the olfactory bulb was significantly lower in the olfactory-impaired patients than in healthy volunteers. The migration of 201Tl to the olfactory bulb was significantly correlated with odor recognition thresholds obtained with T&T olfactometry and correlated with the volume of the olfactory bulb determined from MRI images when all subjects were included. Conclusions: Assessment of the 201Tl migration to the olfactory bulb was the new method for the evaluation of the olfactory nerve connectivity in patients with impaired olfaction. © 2013 Shiga et al