MDPI AGActa Medica Okayama1999-49231812026Streamlined Radiosynthesis of [18F]Fluproxadine (AF78): An Unprotected Guanidine Precursor Enables Efficient One-Step, Automation-Ready Labeling for Clinical Use123ENXinyuChenNuclear Medicine, Faculty of Medicine, University of AugsburgKaitoOhtaFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHiroyukiKimuraAgency for Health, Safety and Environment, Kyoto UniversityYusukeYagiFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTakanoriSasakiFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityNaokoNoseFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMasaruAkehiFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTomohikoYamaneDepartment of Molecular Imaging Research, Kobe City Medical Center General HospitalRudolf A.WernerDepartment of Nuclear Medicine, LMU Hospital, and German Cancer Consortium (DKTK), Partner Site Munich, Ludwig-Maximilians-University of MunichTakahiroHiguchiFaculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityBackground/Objectives: [18F]Fluproxadine (formerly [18F]AF78) is a PET radiotracer targeting the norepinephrine transporter (NET) with potential applications in cardiac, neurological, and oncological imaging. Its guanidine moiety, while essential for NET binding, presents major radiosynthetic challenges due to high basicity and the harsh deprotection conditions required for protected precursors. Previous methods relied on multistep procedures, strong acids, and complex purification, limiting clinical translation. This study aimed to develop a practical one-step radiosynthesis suitable for routine and automated production. Methods: A direct SN2-type nucleophilic [18F]fluorination was performed using an unprotected guanidine precursor to eliminate deprotection steps. Reaction parameters, including the base system, solvent composition, precursor concentration, and temperature, were optimized under conventional and microwave heating. Radiochemical conversion (RCC) and operational robustness were evaluated, and purification strategies were assessed for automation compatibility. Results: Direct [18F]fluorination using the unprotected precursor reduced the total synthesis time to 60–70 min. Optimal conditions employed a tert-butanol/acetonitrile (4:1) solvent system with K2CO3/Kryptofix222, affording RCC up to 33% under conventional heating. Microwave irradiation further improved efficiency, achieving RCC of up to 64% within 1.5 min at 140 C. The method showed broad tolerance to variations in the base molar ratio and precursor concentration and enabled isocratic HPLC purification. Conclusions: This one-step radiosynthesis overcomes longstanding challenges in [18F]fluproxadine production by eliminating harsh deprotection and enabling high-yield, automation-ready synthesis, thereby improving clinical feasibility.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama0969-8051144-1452025Investigating the fate of Zirconium-89 labelled antibody in cynomolgus macaques109001ENTakanoriSasakiFaculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversitySadaakiKimuraAstellas Pharma Inc.AkihiroNodaAstellas Pharma Inc.YoshihiroMurakamiAstellas Pharma Inc.SosukeMiyoshiAstellas Pharma Inc.MasaruAkehiFaculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityKazuhikoOchiaiSchool of Veterinary Nursing and Technology, Faculty of Veterinary Science, Nippon Veterinary and Life Science UniversityMasamiWatanabeFaculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityTakahiroHiguchiFaculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityEijiMatsuuraFaculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityBackground: Preclinical pharmacokinetic studies of therapeutic antibodies in non-human primates are desired because of the difficulty in extrapolating ADME data from animal models to humans. We evaluated the pharmacokinetics of 89Zr (Zirconium-89) -labelled anti-KLH human IgG and its metabolites to confirm their non-specific/physiological accumulation in healthy cynomolgus macaques. The anti-KLH antibody was used as a negative control, ensuring that the observed distribution reflected general IgG behavior rather than antigen-specific accumulation. This provides a valuable reference for comparing the biodistribution of targeted antibodies.<br>
Methods: Selected IgG was conjugated to desferrioxamine (DFO), labelled with 89Zr, and injected into healthy cynomolgus macaques. PET/CT images at the whole-body level were acquired at different time points, and standard uptake values (SUV) in regions of interest, such as the heart, liver, spleen, kidneys, bone, and muscles, were calculated. The distribution of a shortened antibody variant, 89Zr-labelled Fab, as well as that of [89Zr]Zr-DFO and [89Zr]Zr-oxalate, the expected metabolites of 89Zr- labelled IgG, was also assessed.<br>
Results: After 89Zr-labelled IgG injection, the SUV in the heart, vertebral body, and muscle decreased, in line with the 89Zr concentration decrease in the circulation, whereas radioactivity increased over time in the kidneys and liver. Autoradiography of the renal sections indicated that most of the 89Zr- labelled IgG radioactivity accumulated in the renal cortex. Relatively high accumulation in the kidneys was also observed in 89Zr- labelled Fab-injected macaques, and renal autoradiographs of these animals showed that the renal cortex was the preferred accumulation site. However, [89Zr]Zr-DFO was rapidly excreted into the urine, whereas [89Zr]Zr-oxalate was highly accumulated in the epiphysis of the long bones and vertebral body.<br>
Conclusion: In the non-human primate cynomolgus macaque, 89Zr- labelled IgG accumulated in the kidneys and the liver. However, [89Zr]Zr-DFO and 89Zr did not accumulate in these organs. This preclinical pharmacokinetic study performed with human IgG in a non-human primate model using PET is of great significance as it sheds light on the basic fate and distribution of 89Zr- labelled IgG.No potential conflict of interest relevant to this article was reported.Frontiers MediaActa Medica Okayama2297-055X102023In vivo tracking transplanted cardiomyocytes derived from human induced pluripotent stem cells using nuclear medicine imaging1261330ENYukihiroSaitoDepartment of Cardiovascular Medicine, Okayama University HospitalNaokoNoseMolecular Imaging Project of RECTOR Program, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityToshihiroIidaDepartment of Cardiovascular Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKaoruAkazawaDepartment of Cardiovascular Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTakayukiKannoMolecular Imaging Project of RECTOR Program, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYukiFujimotoMolecular Imaging Project of RECTOR Program, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityTakanoriSasakiOkayama Medical Innovation Center, Faculty of Medicine, Dentistry and Pharmaceutical SciencesMasaruAkehiOkayama Medical Innovation Center, Faculty of Medicine, Dentistry and Pharmaceutical SciencesTakahiroHiguchiMolecular Imaging Project of RECTOR Program, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversitySatoshiAkagiDepartment of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMasashiYoshidaDepartment of Chronic Kidney Disease and Cardiovascular Disease, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityToruMiyoshiDepartment of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHiroshiItoDepartment of General Internal Medicine 3, Kawasaki Medical SchoolKazufumiNakamuraDepartment of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityIntroduction: Transplantation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a promising treatment for heart failure. Information on long-term cell engraftment after transplantation is clinically important. However, clinically applicable evaluation methods have not yet been established.<br>
Methods: In this study, to noninvasively assess transplanted cell engraftment, human SLC5A5, which encodes a sodium/iodide symporter (NIS) that transports radioactive tracers such as 125I, 18F-tetrafluoroborate (TFB), and 99mTc-pertechnetate (99mTcO4|), was transduced into human induced pluripotent stem cells (iPSCs), and nuclear medicine imaging was used to track engrafted human iPSC-CMs.<br>
Results: To evaluate the pluripotency of NIS-expressing human iPSCs, they were subcutaneously transplanted into immunodeficient rats. Teratomas were detected by 99mTcO4| single photon emission computed tomography (SPECT/CT) imaging. NIS expression and the uptake ability of 125I were maintained in purified human iPSC-CMs. NIS-expressing human iPSC-CMs transplanted into immunodeficient rats could be detected over time using 99mTcO4| SPECT/CT imaging. Unexpectedly, NIS expression affected cell proliferation of human iPSCs and iPSC-derived cells.<br>
Discussion: Such functionally designed iPSC-CMs have potential clinical applications as a noninvasive method of grafted cell evaluation, but further studies are needed to determine the effects of NIS transduction on cellular characteristics and functions.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2073-440911202022Novel Self-Forming Nanosized DDS Particles for BNCT: Utilizing A Hydrophobic Boron Cluster and Its Molecular Glue Effect3307ENAbdul BasithFithroniDepartment of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityKazukoKobayashiCollaborative Research Center for OMIC, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityHirotakaUjiDepartment of Material Chemistry, Graduate School of Engineering, Kyoto UniversityManabuIshimotoFukushima SiC Applied Engineering Inc.MasaruAkehiCollaborative Research Center for OMIC, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityTakashiOhtsukiDepartment of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityEijiMatsuuraDepartment of Cell Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityBNCT is a non-invasive cancer therapy that allows for cancer cell death without harming adjacent cells. However, the application is limited, owing to the challenges of working with clinically approved boron (B) compounds and drug delivery systems (DDS). To address the issues, we developed self-forming nanoparticles consisting of a biodegradable polymer, namely, "AB-type Lactosome (AB-Lac)" loaded with B compounds. Three carborane isomers (o-, m-, and p-carborane) and three related alkylated derivatives, i.e., 1,2-dimethy-o-carborane (diC1-Carb), 1,2-dihexyl-o-carborane (diC6-Carb), and 1,2-didodecyl-o-carborane (diC12-Carb), were separately loaded. diC6-Carb was highly loaded with AB-Lac particles, and their stability indicated the "molecular glue" effect. The efficiency of in vitro B uptake of diC6-Carb for BNCT was confirmed at non-cytotoxic concentration in several cancer cell lines. In vivo/ex vivo biodistribution studies indicated that the AB-Lac particles were remarkably accumulated within 72 h post-injection in the tumor lesions of mice bearing syngeneic breast cancer (4T1) cells, but the maximum accumulation was reached at 12 h. In ex vivo B biodistribution, the ratios of tumor/normal tissue (T/N) and tumor/blood (T/Bl) of the diC6-Carb-loaded particles remained stably high up to 72 h. Therefore, we propose the diC6-Carb-loaded AB-Lac particles as a promising candidate medicine for BNCT.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2075-17291122021A Novel 89Zr-labeled DDS Device Utilizing Human IgG Variant (scFv): gLactosomeh Nanoparticle-Based Theranostics for PET Imaging and Targeted Therapy158ENMelissa Siaw HanLimDepartment of Cell Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityTakashiOhtsukiDepartment of Interdisciplinary Science and Engineering in Health Systems, Okayama UniversityFumiakiTakenakaCollaborative Research Centre for OMIC, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityKazukoKobayashiCollaborative Research Centre for OMIC, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityMasaruAkehiCollaborative Research Centre for OMIC, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityHirotakaUjiDepartment of Material Chemistry, Graduate School of Engineering, Kyoto UniversityHirotsuguKobuchiDepartment of Cell Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityTakanoriSasakiCollaborative Research Centre for OMIC, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversityEiichiOzekiTechnology Research Laboratory, Shimadzu CorporationEijiMatsuuraDepartment of Cell Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama UniversitygTheranostics,h a new concept of medical advances featuring a fusion of therapeutic and diagnostic systems, provides promising prospects in personalized medicine, especially cancer. The theranostics system comprises a novel 89Zr-labeled drug delivery system (DDS), derived from the novel biodegradable polymeric micelle, gLactosomeh nanoparticles conjugated with specific shortened IgG variant, and aims to successfully deliver therapeutically effective molecules, such as the apoptosis-inducing small interfering RNA (siRNA) intracellularly while offering simultaneous tumor visualization via PET imaging. A 27 kDa-human single chain variable fragment (scFv) of IgG to establish clinically applicable PET imaging and theranostics in cancer medicine was fabricated to target mesothelin (MSLN), a 40 kDa-differentiation-related cell surface glycoprotein antigen, which is frequently and highly expressed by malignant tumors. This system coupled with the cell penetrating peptide (CPP)-modified and photosensitizer (e.g., 5, 10, 15, 20-tetrakis (4-aminophenyl) porphyrin (TPP))-loaded Lactosome particles for photochemical internalized (PCI) driven intracellular siRNA delivery and the combination of 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) offers a promising nano-theranostic-based cancer therapy via its targeted apoptosis-inducing feature. This review focuses on the combined advances in nanotechnology and material sciences utilizing the g89Zr-labeled CPP and TPP-loaded Lactosome particlesh and future directions based on important milestones and recent developments in this platform. No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7012016The Function of 2-glycoprotein I in Angiogenesis and Its in Vivo Distribution in Tumor Xenografts1324ENArum Tri WahyuningsihLianhuaShenKazukoKobayashiTakanoriSasakiFumiakiTakenakaTakahisaHanadaMasaruAkehiAkiyaAkahoshiEiichiOzekiEijiAndoEijiMatsuuraOriginal Article/10.18926/AMO/53999Intact 2-glycoprotein I (i2GPI) is a glycoprotein that regulates coagulation and fibrinolysis. Nicked 2GPI (n2GPI) possesses an angiogenic property at a relatively low concentration, and an antiangiogenic property at a high concentration. Here we investigated the functions of i 2GPI and n2GPI in vascular endothelial growth factor (VEGF)-A-induced endothelial cell proliferation and tube formation. We used noninvasive PET imaging to analyze the in vivo distribution of intravenously injected 2GPI variants in tumor lesions in mice. i2GPI was incubated with plasmin to obtain n2GPI, and its N-terminal sequence was analyzed. n2GPI had at least one other cleavage site upstream of the 2GPIʼs domain V, whereas the former plasmin-cleavage site locates between K317 and T318. Both of intact and nicked 2GPI significantly inhibited the VEGF-A-induced cell proliferation and the tube formation of human umbilical vein endothelial cells (HUVECs). PET imaging visualized considerably distributed intensities of all tested 2GPI variants in tumor lesions of pancreatic tumor cell-xenografts. These results indicate that 2GPI may be physiologically and pathophysiologically important in the regulation of not only coagulation and fibrinolysis, but also angiogenesis.No potential conflict of interest relevant to this article was reported.