2025/03/31 更新

写真a

ニシイ リュウイチ
西井 龍一
NISHII Ryuichi
所属
大学院医学系研究科 総合保健学専攻 バイオメディカルイメージング情報科学 教授
大学院担当
大学院医学系研究科
学部担当
医学部(保健学科)
職名
教授
外部リンク

学位 1

  1. 博士(医学) ( 2000年3月   宮崎医科大学 ) 

研究分野 1

  1. ライフサイエンス / 放射線科学

 

論文 16

  1. A Monte Carlo study comparing dead-time losses of a gamma camera between tungsten functional paper and lead sheet for dosimetry in targeted radionuclide therapy with Lu-177 Open Access

    Nakanishi, K; Fujita, N; Iwanaga, H; Asano, Y; Abe, S; Nishii, R; Kato, K

    ANNALS OF NUCLEAR MEDICINE   39 巻 ( 2 ) 頁: 199 - 207   2025年2月

     詳細を見る

    記述言語:英語   出版者・発行元:Annals of Nuclear Medicine  

    Objective: Dead-time loss is reported to be non-negligible for some patients with a high tumor burden in Lu-177 radionuclide therapy, even if the administered activity is 7.4 GBq. Hence, we proposed a simple method to shorten the apparent dead time and reduce dead-time loss using a thin lead sheet in previous work. The collimator surface of the gamma camera was covered with a lead sheet in our proposed method. While allowing the detection of 208-keV gamma photons of Lu-177 that penetrate the sheet, photons with energies lower than 208 keV, which cause dead-time loss, were shielded. In this study, we evaluated the usefulness of tungsten functional paper (TFP) for the proposed method using Monte Carlo simulation. Methods: The count rates in imaging of Lu-177 administered to patients were simulated with the International Commission on Radiological Protection (ICRP) 110 phantom using the GATE Monte Carlo simulation toolkit. The simulated gamma cameras with a 0.5-mm lead sheet, 1.2-mm TFP, or no filter were positioned closely on the anterior and posterior sides of the phantom. The apparent dead times and dead-time losses at 24 h after administration were calculated for an energy window of 208 keV ± 10%. Moreover, the dead-time losses at 24–120 h were analytically assessed using activity excretion data of Lu-177-DOTATATE. Results: The dead-time loss without a filter was 5% even 120 h after administration in patients with a high tumor burden and slow excretion, while those with a lead sheet and TFP were 0.22 and 0.58 times less than those with no filter, respectively. The count rates with the TFP were 1.3 times higher than those with the lead sheet, and the TFP could maintain primary count rates at 91–94% of those without a filter. Conclusions: Although the apparent dead time and dead-time loss with the lead sheet were shorter and less than those with TFP, those with TFP were superior to those without a filter. The advantage of TFP over the lead sheet is that the decrease in primary count rates was less.

    DOI: 10.1007/s12149-024-01987-5

    Open Access

    Web of Science

    Scopus

    PubMed

  2. Deep Learning-based Whole-liver Segmentation Using only <SUP>18</SUP>F-FDG PET Images

    Yamao, T; Kaneko, Y; Miwa, K; Miyaji, N; Nishii, R; Yamazaki, K; Higashi, T

    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING   51 巻   頁: S313 - S314   2024年9月

     詳細を見る

  3. Expression of fibroblast activation protein- α in human deep vein thrombosis

    Oguri, N; Gi, T; Nakamura, E; Furukoji, E; Goto, H; Maekawa, K; Tsuji, AB; Nishii, R; Aman, M; Moriguchi-Goto, S; Sakae, T; Azuma, M; Yamashita, A

    THROMBOSIS RESEARCH   241 巻   頁: 109075   2024年9月

     詳細を見る

    記述言語:英語   出版者・発行元:Thrombosis Research  

    Background: Fibroblast activation protein-α (FAP), a type-II transmembrane serine protease, is associated with wound healing, cancer-associated fibroblasts, and chronic fibrosing diseases. However, its expression in deep vein thrombosis (DVT) remains unclear. Therefore, this study investigated FAP expression and localization in DVT. Methods: We performed pathological analyses of the aspirated thrombi of patients with DVT (n = 14), classifying thrombotic areas in terms of fresh, cellular lysis, and organizing reaction components. The organizing reaction included endothelialization and fibroblastic reaction. We immunohistochemically examined FAP-expressed areas and cells, and finally analyzed FAP expression in cultured dermal fibroblasts. Results: All the aspirated thrombi showed a heterogeneous mixture of at least two of the three thrombotic areas. Specifically, 83 % of aspirated thrombi showed fresh and organizing reaction components. Immunohistochemical expression of FAP was restricted to the organizing area. Double immunofluorescence staining showed that FAP in the thrombi was mainly expressed in vimentin-positive or α-smooth muscle actin-positive fibroblasts. Some CD163-positive macrophages expressed FAP. FAP mRNA and protein levels were higher in fibroblasts with low-proliferative activity cultured under 0.1 % fetal bovine serum (FBS) than that under 10 % FBS. Fibroblasts cultured in 10 % FBS showed a significant decrease in FAP mRNA levels following supplementation with hemin, but not with thrombin. Conclusions: The heterogeneous composition of venous thrombi suggests a multistep thrombus formation process in human DVT. Further, fibroblasts or myofibroblasts may express FAP during the organizing process. FAP expression may be higher in fibroblasts with low proliferative activity.

    DOI: 10.1016/j.thromres.2024.109075

    Web of Science

    Scopus

    PubMed

  4. Unique advantages of dynamic <sc>l</sc>-[<SUP>11</SUP>C]methionine PET/CT for assessing the rate of skeletal muscle protein synthesis: A pilot trial in young men Open Access

    Sumi, K; Yamazaki, K; Nishii, R; Sakuda, M; Nakamura, K; Ashida, K; Tamura, K; Higashi, T

    PLOS ONE   19 巻 ( 7 ) 頁: e0305620   2024年7月

     詳細を見る

    記述言語:英語   出版者・発行元:PLoS ONE  

    Although the standard method to evaluate skeletal muscle protein synthesis (MPS) is muscle biopsy, the method is invasive and problematic for multisite use. We conducted a small pilot study in volunteers to investigate changes in MPS according to skeletal muscle site using a noninvasive method in which 6 healthy young men were given yogurt (containing 20 g milk protein) or water, and 1 h later, L-[11C]methionine ([11C]Met) was administered intravenously. Dynamic PET/CT imaging of their thighs was performed for 60 min. The influx constant Ki of [11C]Met in skeletal muscle protein was calculated as an index of MPS using a Patlak plot, and found to be 0.6%–28% higher after ingesting yogurt than after water in 5 of the 6 volunteer participants, but it was 34% lower in the remaining participant. Overall, this indicated no significant increase in Ki after ingesting milk protein. However, when the quadriceps and hamstring muscles were analyzed separately, we found a significant difference in Ki. This demonstrates the potential of visualizing MPS by calculating the Ki for each voxel and reconstructing it as an image, which presents unique advantages of [11C]Met PET/CT for evaluating MPS, such as site-specificity and visualization.

    DOI: 10.1371/journal.pone.0305620

    Open Access

    Web of Science

    Scopus

    PubMed

  5. Potential Application of the Myocardial Scintigraphy Agent [<SUP>123</SUP>I]BMIPP in Colon Cancer Cell Imaging

    Sato, K; Hirayama, Y; Mizutani, A; Yao, JW; Higashino, J; Kamitaka, Y; Muranaka, Y; Yamazaki, K; Nishii, R; Kobayashi, M; Kawai, K

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   25 巻 ( 14 )   2024年7月

     詳細を見る

    記述言語:英語   出版者・発行元:International Journal of Molecular Sciences  

    [123I]β-methyl-p-iodophenyl-pentadecanoic acid ([123I]BMIPP), which is used for nuclear medicine imaging of myocardial fatty acid metabolism, accumulates in cancer cells. However, the mechanism of accumulation remains unknown. Therefore, this study aimed to elucidate the accumulation and accumulation mechanism of [123I]BMIPP in cancer cells. We compared the accumulation of [123I]BMIPP in cancer cells with that of [18F]FDG and found that [123I]BMIPP was a much higher accumulation than [18F]FDG. The accumulation of [123I]BMIPP was evaluated in the presence of sulfosuccinimidyl oleate (SSO), a CD36 inhibitor, and lipofermata, a fatty acid transport protein (FATP) inhibitor, under low-temperature conditions and in the presence of etomoxir, a carnitine palmitoyl transferase I (CPT1) inhibitor. The results showed that [123I]BMIPP accumulation was decreased in the presence of SSO and lipofermata in H441, LS180, and DLD-1 cells, suggesting that FATPs and CD36 are involved in [123I]BMIPP uptake in cancer cells. [123I]BMIPP accumulation in all cancer cell lines was significantly decreased at 4 °C compared to that at 37 °C and increased in the presence of etomoxir in all cancer cell lines, suggesting that the accumulation of [123I]BMIPP in cancer cells is metabolically dependent. In a biological distribution study conducted using tumor-bearing mice transplanted with LS180 cells, [123I]BMIPP highly accumulated in not only LS180 cells but also normal tissues and organs (including blood and muscle). The tumor-to-intestine or large intestine ratios of [123I]BMIPP were similar to those of [18F]FDG, and the tumor-to-large-intestine ratios exceeded 1.0 during 30 min after [123I]BMIPP administration in the in vivo study. [123I]BMIPP is taken up by cancer cells via CD36 and FATP and incorporated into mitochondria via CPT1. Therefore, [123I]BMIPP may be useful for imaging cancers with activated fatty acid metabolism, such as colon cancer. However, the development of novel imaging radiotracers based on the chemical structure analog of [123I]BMIPP is needed.

    DOI: 10.3390/ijms25147747

    Web of Science

    Scopus

    PubMed

  6. Development of radioiodine-labeled mequitazine for evaluation of hepatic CYP2D activity Open Access

    Mizutani, A; Kobayashi, M; Nishi, K; Fujita, KI; Takahashi, K; Muranaka, Y; Sato, K; Kitamura, M; Suzuki, C; Nishii, R; Shikano, N; Magata, Y; Ishida, Y; Kunishima, M; Fukuchi, K; Kawai, K

    FRONTIERS IN PHARMACOLOGY   15 巻   頁: 1397288   2024年6月

     詳細を見る

    記述言語:英語   出版者・発行元:Frontiers in Pharmacology  

    Background: As drug-metabolizing enzyme activities are affected by a variety of factors, such as drug-drug interactions, a method to evaluate drug-metabolizing enzyme activities in real time is needed. In this study, we developed a novel SPECT imaging probe for evaluation of hepatic CYP2D activity. Methods: Iodine-123- and 125-labeled 4-iodobenzylmequitazine (123/125I-BMQ) was synthesized with high labeling and purity. CYP isozymes involved in the metabolism of 125I-BMQ in mouse liver microsomes were evaluated, and the utility of 123/125I-was assessed from biological distribution and SPECT imaging evaluation in normal and CYP2D-inhibited mice. Results: In vitro metabolite analysis using mouse liver microsomes showed that 125I-BMQ is specifically metabolized by CYP2D. Biological distribution and SPECT imaging of 123/125I-BMQ in normal mice showed that injection 123/125I-BMQ accumulated early in the liver and was excreted into the gallbladder and intestines. In CYP2D-inhibited mice, accumulation in the liver was increased, but accumulation in the gallbladder and intestines, the excretory organ, was delayed. Since only metabolites of 125I-BMQ are detected in bile, visualization and measuring of the accumulation of metabolites over time in the intestine, where bile is excreted, could predict the amount of metabolites produced in the body and evaluate CYP2D activity, which would be useful in determining the dosage of various drugs metabolized by CYP2D. Conclusion: 123/125I-BMQ is useful as a SPECT imaging probe for comprehensive and direct assessment of hepatic CYP2D activity in a minimally invasive and simple approach.

    DOI: 10.3389/fphar.2024.1397288

    Open Access

    Web of Science

    Scopus

    PubMed

  7. Age-related Variation in SUVR in 11C-PiB PET Scans

    Inagaki, T; Fujita, N; Tada, T; Ikeda, H; Inagaki, T; Isobe, R; Nagahara, T; Abe, S; Nakanishi, K; Nishii, R; Kato, K

    JOURNAL OF NUCLEAR MEDICINE   65 巻   2024年6月

     詳細を見る

  8. Comparison of image reconstruction methods by a SPECT phantom using an inkjet printer

    Nagahara, T; Fujita, N; Katafuchi, T; Ikeda, H; Nakanishi, K; Nishii, R; Isobe, R; Inagaki, T; Tsunekawa, R; Kato, K

    JOURNAL OF NUCLEAR MEDICINE   65 巻   2024年6月

     詳細を見る

  9. Initial assessment of biodistribution in healthy males using 11C-MePro PET/CT and exploratory analysis of pancreatic molecular pathology

    Yamazaki, K; Nishii, R; Tani, K; Hashimoto, H; Sudo, H; Tsuji, A; Sato, S; Higashi, T

    JOURNAL OF NUCLEAR MEDICINE   65 巻   2024年6月

     詳細を見る

  10. Relationship between 99mTc-MAA Planar Image Accumulation Distribution in Pulmonary Hypertension and Indices Obtained by Right Heart Catheterization

    Tsunekawa, R; Fujita, N; Ikeda, H; Nakanishi, K; Nishii, R; Inagaki, T; Isobe, R; Nagahara, T; Inagaki, T; Abe, S; Kato, K

    JOURNAL OF NUCLEAR MEDICINE   65 巻   2024年6月

     詳細を見る

  11. A simple method to shorten the apparent dead time in the dosimetry of Lu-177 for targeted radionuclide therapy using a gamma camera

    Nakanishi, K; Fujita, N; Abe, S; Nishii, R; Kato, K

    PHYSICA MEDICA-EUROPEAN JOURNAL OF MEDICAL PHYSICS   119 巻   頁: 103298   2024年3月

     詳細を見る

    記述言語:英語   出版者・発行元:Physica Medica  

    Background: The dead-time loss reportedly degrades the accuracy of dosimetry using a gamma camera for targeted radionuclide therapy with Lu-177; therefore, the dead-time loss needs to be corrected. However, the correction is challenging. In this study, we propose a novel and simple method to shorten the apparent dead time rather than correcting it through experiments and Monte Carlo simulations. Methods: An energy window of 208 keV ± 10 % is generally used for the imaging of Lu-177. Lower-energy gamma photons and X-rays of Lu-177 do not contribute to image formation but lead to dead-time losses. In our proposed method, a thin lead sheet was used to shield gamma photons and X-rays with energies lower than 208 keV, while detecting 208 keV gamma photons that penetrated the thin sheet. We measured and simulated the energy spectra and count rate characteristics of a clinical gamma camera system using a cylindrical phantom filled with a Lu-177 solution. Lead sheets of 1.0- and 0.5-mm thicknesses were used as thin shields, and the dead-time losses in tumour imaging with consumed Lu-177 were simulated. Results: The apparent dead times with lead sheets of 1.0- and 0.5-mm thicknesses and without a lead sheet were 1.7, 1.9, and 5.8 µs for an energy window of 208 keV ± 10 %, respectively. The dead-time losses could be reduced from 10 % to 1.3 % using the 1.0-mm thick lead sheet in the simulated imaging of tumour. Conclusion: Our method is promising in clinical situations and studies on Lu-177 dosimetry for tumours.

    DOI: 10.1016/j.ejmp.2024.103298

    Web of Science

    Scopus

    PubMed

  12. Synthesis and evaluation of a rociletinib analog as prospective imaging double mutation L858R/T790M in non-small cell lung cancer

    Fawwaz, M; Mishiro, K; Purwono, B; Nishii, R; Ogawa, K

    JOURNAL OF PHARMACY & PHARMACOGNOSY RESEARCH   12 巻 ( 2 ) 頁: 231 - 242   2024年3月

     詳細を見る

    出版者・発行元:Journal of Pharmacy and Pharmacognosy Research  

    Context: Imaging the mutation status of non-small cell lung cancer (NSCLC) using radiolabeled tyrosine kinase inhibitor (TKI) analogs has garnered interest due to their unique interactions with the target epidermal growth factor receptor (EGFR). Rociletinib is a third-generation TKI that selectively inhibits the activated EGFR L858R/T790M mutations while sparing the wild-type EGFR. Aims: To synthesize a rociletinib analog for radioiodination purposes and evaluate its affinity for EGFR L858R/T790M using molecular docking and in vitro cytotoxicity assay. Methods: The rociletinib analog, N-{3-[(4-{[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino}-5-(trifluoromethyl)pyrimidine-2-yl)amino] -5-iodophenyl} acrylamide (I-RMFZ), was produced by adding iodine into the diaminophenyl group and changing the position of the trifluoromethyl group. A simulation of molecular docking was conducted using the AutoDock Vina software suite. IC50 of I-RMFZ was determined using a cell cytotoxicity assay. Results: I-RMFZ was successfully synthesized through multistep reactions. Molecular docking revealed that I-RMFZ interacts with the EGFR L858R/T790M mutation. Cytotoxicity assay demonstrated that I-RMFZ had a high selectivity towards EGFR L858R/T779M mutation. Conclusions: I-RMFZ is notable for radioiodination and is anticipated to be comparable with in vivo features of rociletinib. Thus, I-RMFZ can potentially be developed as an imaging agent for NSCLC through preclinical assay.

    DOI: 10.56499/jppres23.1743_12.2.231

    Web of Science

    Scopus

  13. A first-in-man study of [<SUP>18</SUP>F] FEDAC: a novel PET tracer for the 18-kDa translocator protein

    Tamura, K; Nishii, R; Tani, K; Hashimoto, H; Kawamura, K; Zhang, MR; Maeda, T; Yamazaki, K; Higashi, T; Jinzaki, M

    ANNALS OF NUCLEAR MEDICINE     2024年1月

     詳細を見る

    記述言語:英語   出版者・発行元:Annals of Nuclear Medicine  

    Purpose: N-benzyl-N-methyl-2-[7, 8-dihydro-7-(2-[18F] fluoroethyl) -8-oxo-2-phenyl-9H-purin-9-yl] acetamide ([18F] FEDAC) is a novel positron emission tomography (PET) tracer that targets the translocator protein (TSPO; 18 kDa) in the mitochondrial outer membrane, which is known to be upregulated in various diseases such as malignant tumors, neurodegenerative diseases, and neuroinflammation. This study presents the first attempt to use [18F]FEDAC PET/CT and evaluate its biodistribution as well as the systemic radiation exposure to the radiotracer in humans. Materials and Methods: Seventeen whole-body [18F]FEDAC PET/CT (injected dose, 209.1 ± 6.2 MBq) scans with a dynamic scan of the upper abdomen were performed in seven participants. Volumes of interest were assigned to each organ, and a time–activity curve was created to evaluate the biodistribution of the radiotracer. The effective dose was calculated using IDAC-Dose 2.1. Results: Immediately after the intravenous injection, the radiotracer accumulated significantly in the liver and was subsequently excreted into the gastrointestinal tract through the biliary tract. It also showed high levels of accumulation in the kidneys, but showed minimal migration to the urinary bladder. Thus, the liver was the principal organ that eliminated [18F] FEDAC. Accumulation in the normal brain tissue was minimal. The effective dose estimated from biodistribution in humans was 19.47 ± 1.08 µSv/MBq, and was 3.60 mSV for 185 MBq dose. Conclusion: [18F]FEDAC PET/CT provided adequate image quality at an acceptable effective dose with no adverse effects. Therefore, [18F]FEDAC may be useful in human TSPO-PET imaging.

    DOI: 10.1007/s12149-023-01895-0

    Web of Science

    Scopus

    PubMed

  14. Synthesis and initial <i>in vitro</i> evaluation of olmutinib derivatives as prospective imaging probe for non-small cell lung cancer

    Fawwaz, M; Mishiro, K; Arwansyah; Nishii, R; Ogawa, K

    BIOIMPACTS   14 巻 ( 1 ) 頁: 27774   2024年1月

     詳細を見る

    記述言語:英語   出版者・発行元:BioImpacts  

    Introduction: Imaging a non-small cell lung cancer (NSCLC) using radiolabeled tyrosine kinase inhibitors (TKIs) has attracted attention due to their unique interaction with the target epidermal growth factor receptor (EGFR). Olmutinib (OTB) is one of the third-generation EGFR TKIs, which selectively inhibit EGFR L858R/T790M mutation. In this study, we aim to estimate the interaction of the iodinated OTB (I-OTB)-receptor complex by molecular docking. Furthermore, we will synthesize the I-OTB and evaluate its activity toward EGFR L858R/T790M by in vitro cytotoxicity assay. Methods: A molecular docking simulation was carried out using an AutoDock Vina program package to estimate the interaction of the ligand-receptor complex. The I-OTB, N-{3-iodo-5-[(2- {[4-(4-methylpiperazin-1-yl)phenyl]aminothieno{3,2-d}pyrimidin-4-yl)oxy]phenyl} acrylamide, was synthesized by introducing an iodine atom in the phenyl group in the 3-aryloxyanilide structure. The half inhibitory concentration (IC50) was determined by employing a 2-(2-methoxy- 4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium monosodium salt (WST- 8) assay to evaluate the activity of I-OTB. Results: The docking study exhibited that I-OTB could take an interaction similar to that of the parent compound. We successfully synthesized I-OTB and confirmed its structure by instrumental analysis. The binding energy of OTB and I-OTB in complex with EGFR T790M are -8.7 and -7.9 kcal/mol, respectively. The cytotoxicity assay showed that I-OTB also has an affinity towards the EGFR L858R/T790M mutation with the IC50 10.49 ± 5.64 μM compared to the EGFR wild type with the IC50 over than 10 μM. Conclusion: The cytotoxicity effect of I-OTB was comparable to that of OTB. This result indicates that the iodine substituent in OTB did not alter the parent compound selectivity toward double mutations EGFR L858R/T790M. Therefore, I-OTB is prominent for radioiodination, and [123/124I] I-OTB may be a promising candidate for EGFR L858R/T790M mutation imaging.

    DOI: 10.34172/bi.2023.27774

    Web of Science

    Scopus

    PubMed

  15. 膵癌早期検出に向けた新規PET/CTイメージング -アミノ酸トランスポーター発現に応じた個別化画像診断への取り組み- 査読有り

    西井 龍一, 須藤 仁美

    Precision Medicine   7 巻   頁: 60 - 63   2024年

     詳細を見る

  16. 膵がん早期発見に向けた新規PET/CT画像診断法の開発ー11C-MeLeu PET/CT及び11C-MePro PET/CTー

    西井 龍一, 須藤 仁美

    BIO Clinica   38 巻   頁: 52 - 55   2023年

     詳細を見る

▼全件表示

科研費 4

  1. 新規アミノ酸PET薬剤を用いた脳腫瘍の分子イメージング研究

    研究課題/研究課題番号:23K07085  2023年4月 - 2026年3月

    科学研究費助成事業  基盤研究(C)

    山本 由佳, 須藤 仁美, 西山 佳宏, 西井 龍一, 畠山 哲宗, 則兼 敬志

      詳細を見る

    担当区分:研究分担者 

    脳腫瘍は予後不良でその分子生物学的特徴を明らかにするため、アミノ酸PET薬剤の11C-METを用いたPET検査が行われることが多い。しかし、遺伝子変異の有無などの予測法はまだ確立されていない。
    新規アミノ酸PET薬剤である11C-MeLeuを脳腫瘍に応用し、最適な検査法の確立、脳腫瘍でのSLC6A20との関係を明らかにする。また、悪性度評価、遺伝子変異の有無などとの関係を調べ、従来の11C-MET PETと比べてこれら診断能が向上できるかを検討する。腫瘍特異的なPET検査を行うことで、脳腫瘍の診断能の向上と生物学的特徴の把握が容易になり、最適な診断法の確立に繋がる。

  2. 膵癌特異的トランスポーター標的[11C]MEPROによるPET/CT臨床研究

    研究課題/研究課題番号:23K07170  2023年4月 - 2026年3月

    科学研究費助成事業  基盤研究(C)

    西井 龍一, 須藤 仁美, 山崎 香奈

      詳細を見る

    担当区分:研究代表者 

    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    本研究は膵癌特異的アミノ酸トランスポーターを標的として新たに開発された人工アミノ酸製剤 [11C]MEPROを用いた早期膵癌発見のためのPET臨床研究である。本研究では、新規アミノ酸PET/CTによるFirst-in-human試験及び膵癌患者対象の臨床研究を実施する。現在膵癌診断に広く使用されるCT、MRI、FDG-PET/CTなどの画像診断の限界を克服する早期膵癌診断開発であり、まさに膵癌生存率向上という「アンメット・メディカル・ニーズ」に応える研究であると考える。
    特定臨床研究「健康成人を対象とした新規膵癌PETプローブ[11C]MeProの安全性及び薬物動態に関する試験」(jRCTs031210472)として開始した。単一群/非盲検/非対照/単群比較/診断目的で実施した。脱落者はおらず、6名のデータを収集した時点で探索的なデータ解析は可能と判断し、6名で登録ならびに試験実施を終了した。[11C] MePro投与後、自覚症状や採血・生理学的データを含む他覚的所見に変化はなく、有害事象発生はなかった。[11C]MePro投与後1分以内に血液(心内腔)の取り込みはSUVmean; 30.9±12.0に達し、速やかに低下した。腎の集積は投与20分後にSUVmean; 16.7±3.1とピークに達し、撮像時間内の90分後まで同程度の集積を維持していた。膵への集積は投与後一貫して低く、20分後でSUVmean; 2.4±0.2、40分後でもSUVmean; 2.4±0.2であった。肝、脳などその他主要臓器への集積も低値であった。
    当初の計画通り、新規PETイメージングの臨床応用を特定臨床研究として開始できた。研究参加登録も6名であり臨床評価に値する。現在までヒト試験での副反応は観察されず、画像試験も順調に終了。臨床画像化検討、被ばく線量評価も順調に検討中である。
    被験者6名について全身実効線量や各臓器の被ばく線量を最終的にまとめる。膵癌患者のPET画像検査での至適撮影条件(撮影時間や撮影回数など)を第I相試験結果を用いて検討する。膵癌患者を対象とした臨床第II相試験を計画し実施する。膵癌組織標本を用いたトランスポータ発現解析をすすめていく。

  3. がん特異的グルタミノリシスを利用したミトコンドリア標的セラノスティクス薬剤の開発

    研究課題/研究課題番号:22K19504  2022年6月 - 2025年3月

    科学研究費助成事業  挑戦的研究(萌芽)

    小林 正和, 水谷 明日香, 国嶋 崇隆, 西井 龍一, 川井 恵一

      詳細を見る

    担当区分:研究分担者 

    本研究では、がん関連アミノ酸トランスポーターASCT2により細胞内に取り込まれた後、ミトコンドリア内でグルタミナーゼ (GLS)が寄与してがん細胞内で代謝トラッピングが生じる核医学画像診断及び治療薬の開発を目指す。この目的を達成するため、1) ASCT2とGLSの基質・阻害剤探索、2) 標識原料の合成、3) 核医学画像診断薬の開発、4) 核医学治療薬剤の開発、この4つの実験計画に従って実施する。
    本研究では、がん細胞におけるグルタミノリシス経路の可視化とミトコンドリアDNA標的治療法の確立を目指し、当該経路で特異的に亢進するアミノ酸トランスポーターASCT2とグルタミナーゼ (GLS)に高親和性を有する新規核医学セラノスティクス薬剤を開発することを目的とした。がん細胞では、「ワールブルク効果」と呼ばれる解糖系の代謝亢進が起きていることは古くから知られているが、糖代謝と関連の深いアミノ酸代謝にも劇的な代謝亢進が起こることが明らかになった。特に、がんに特異的なアミノ酸代謝として、「グルタミノリシス」が注目されているがんのグルタミノリシスとは、ASCT2によって細胞内に取り込まれたグルタミンがミトコンドリア内の代謝酵素GLSによってグルタミン酸に変換後、乳酸に分解される経路である。GLSが特異的に亢進するがん細胞において、抗酸化作用をもたらすグルタチオンが大量生成し、抗がん剤に対する薬剤耐性化が引き起こされるため、グルタミンからGLSによるグルタミン酸への移行量を正確に可視化できれば、がん細胞の薬剤耐性化が観察できる可能性が高いと期待した。このような背景の中、2022年度には、ASCT2やGLSに対して、ある一定レベルの親和性を有する2つの化合物の同定に至ったため、2023年度には、これらをリード化合物とした標識原料を合成した。また、これらの標識原料に対する放射性ヨウ素標識体の合成に成功した。さらに、ヒト由来がん細胞株4種において、これらの放射性ヨウ素標識体の集積量を検討した結果、リアルタイムPCRにおいてASCT2の遺伝子発現量が高かった細胞株において、放射性ヨウ素標識体Gの集積量が高くなった。加えて、阻害剤を用いて検討した結果、ASCTとGLSの寄与が見出されたため細胞集積実験レベルでは、放射性ヨウ素標識体GはASCTにより細胞内に取り込まれ、GLSによりミトコンドリア内に集積する薬剤であると思われた。
    当初の目標通り、2023年度は放射性ヨウ素標識体開発のための標識原料の合成と、放射性ヨウ素標識体の開発を行い、ヒト由来がん細胞株において、その標識体の有効性を評価できた。
    2024年度は、開発した放射性ヨウ素標識体を担がんマウスにおいて評価する予定である。

  4. ナトリウム共役能動輸送型糖輸送体を標的としたセラノスティクス薬剤の開発

    研究課題/研究課題番号:21H02865  2021年4月 - 2025年3月

    科学研究費助成事業  基盤研究(B)

    小林 正和, 水谷 明日香, 国嶋 崇隆, 玉井 郁巳, 川井 恵一, 西井 龍一, 鷲山 幸信

      詳細を見る

    担当区分:研究分担者 

    本研究では、FDG-PET検査の問題点を克服する臨床応用性に優れたSGLT (sodium glucose co-transporter)に高親和性を示す分子標的画像診断薬及び核医学治療薬を開発する。SGLT-1とSGLT-2は、FDGで診断困難な脳腫瘍、膵臓がん、前立腺がんに高発現しているため、FDG-PET検査を補完するSGLT分子標的核医学画像診断薬を開発する。その後、この診断薬を基本骨格とした核医学治療薬を開発する。
    本研究では、18F-FDG (2-deoxy-2-[18F]fluoro-D-glucose)を用いたPET (positron emission tomography)検査の問題点を克服する臨床応用性に優れたNa+共役
    能動輸送型糖輸送体SGLT (sodium glucose co-transporter)に高親和性を示すがん分子標的核医学画像診断薬の開発及び評価法の技術基盤の確立を目的とした。FDGが輸送される促進拡散型糖輸送体GLUT (sodium independent glucose transporter)との相同性がなく、かつ6種のサブタイプを有するSGLTの中でも、FDGでは診断困難な脳腫瘍、膵臓がん、前立腺がんに高発現しているSGLT-1/-2により腫瘍に特異的に高集積する新規SGLT分子標的核医学画像診断薬の開発を試みる。2022年度は、SGLTとGLUTの一過性高発現細胞を用いて、2021年度に開発した2種類のヨウ素標識体がSGLTへの特異性を評価した。方法として、遺伝子導入が容易に可能なヒト胎児腎細胞 HEK293株において、GLUT-1/-3 及び SGLT-1/-2 の各プラスミド DNA を用いてtransfection を行い、グルコース輸送体単一発現細胞を作製し、今回開発したヨウ素標識体の有効性を評価した。その結果、ヨウ素標識体AはSGLT-1/-2の両者に親和性が見られ、GLUTとは親和性が見られなかった、ヨウ素標識体PはSGLT-1のみに親和性があった。2023年度は、これらのヨウ素標識体のがん細胞に対する集積性を評価するとともに、in vitro実験で使用したがん細胞を移植した担がんマウスにおける有効性の検討も試みる。
    当初の予定通り、これまでSGLTに親和性のある母体化合物を見出し、グルコース輸送体単一発現細胞を利用して、その有用性を確認してきた。しかし、2022年度には、ヒト由来がん細胞を用いた検討を行えなかったため、本研究の進展がやや遅れている。
    2023年度は以下の実験手順に従って行う。
    1) 各グルコース輸送体(SGLTとGLUT)の遺伝子発現量を確認したヒト由来がん細胞において、開発したヨウ素標識体の集積性を確認する。
    2) 2022年度行う予定であったブドウ糖誘導体のSGLT輸送系寄与率評価法を確立する。
    3) 新たなヨウ素標識体の開発も試みる。
    4) ヒト由来がん細胞を移植した担がんマウスの作成を行う。