start-ver=1.4 cd-journal=joma no-vol=7 cd-vols= no-issue=1 article-no= start-page=64 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20201102 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Performance evaluation of fifth-generation ultra-high-resolution SPECT system with two stationary detectors and multi-pinhole imaging en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Small-animal single-photon emission computed tomography (SPECT) systems with multi-pinhole collimation and large stationary detectors have advantages compared to systems with moving small detectors. These systems benefit from less labour-intensive maintenance and quality control as fewer prone parts are moving, higher accuracy for focused scans and maintaining high resolution with increased sensitivity due to focused pinholes on the field of view. This study aims to investigate the performance of a novel ultra-high-resolution scanner with two-detector configuration (U-SPECT5-E) and to compare its image quality to a conventional micro-SPECT system with three stationary detectors (U-SPECT+). Methods The new U-SPECT5-E with two stationary detectors was used for acquiring data with Tc-99m-filled point source, hot-rod and uniformity phantoms to analyse sensitivity, spatial resolution, uniformity and contrast-to-noise ratio (CNR). Three dedicated multi-pinhole mouse collimators with 75 pinholes each and 0.25-, 0.60- and 1.00-mm pinholes for extra ultra-high resolution (XUHR-M), general-purpose (GP-M) and ultra-high sensitivity (UHS-M) imaging were examined. For CNR analysis, four different activity ranges representing low- and high-count settings were investigated for all three collimators. The experiments for the performance assessment were repeated with the same GP-M collimator in the three-detector U-SPECT+ for comparison. Results Peak sensitivity was 237 cps/MBq (XUHR-M), 847 cps/MBq (GP-M), 2054 cps/MBq (UHS-M) for U-SPECT5-E and 1710 cps/MBq (GP-M) for U-SPECT+. In the visually analysed sections of the reconstructed mini Derenzo phantoms, rods as small as 0.35 mm (XUHR-M), 0.50 mm (GP-M) for the two-detector as well as the three-detector SPECT and 0.75 mm (UHS-M) were resolved. Uniformity for maximum resolution recorded 40.7% (XUHR-M), 29.1% (GP-M, U-SPECT5-E), 16.3% (GP-M, U-SPECT+) and 23.0% (UHS-M), respectively. UHS-M reached highest CNR values for low-count images; for rods smaller than 0.45 mm, acceptable CNR was only achieved by XUHR-M. GP-M was superior for imaging rods sized from 0.60 to 1.50 mm for intermediate activity concentrations. U-SPECT5-E and U-SPECT+ both provided comparable CNR. Conclusions While uniformity and sensitivity are negatively affected by the absence of a third detector, the investigated U-SPECT5-E system with two stationary detectors delivers excellent spatial resolution and CNR comparable to the performance of an established three-detector-setup. en-copyright= kn-copyright= en-aut-name=HoffmannJan, V en-aut-sei=Hoffmann en-aut-mei=Jan, V kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=JanssenJan P. en-aut-sei=Janssen en-aut-mei=Jan P. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KannoTakayuki en-aut-sei=Kanno en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ShibutaniTakayuki en-aut-sei=Shibutani en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OnoguchiMasahisa en-aut-sei=Onoguchi en-aut-mei=Masahisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=LapaConstantin en-aut-sei=Lapa en-aut-mei=Constantin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=GrunzJan-Peter en-aut-sei=Grunz en-aut-mei=Jan-Peter kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=BuckAndreas K. en-aut-sei=Buck en-aut-mei=Andreas K. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HiguchiTakahiro en-aut-sei=Higuchi en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Nuclear Medicine, University Hospital W?rzburg kn-affil= affil-num=2 en-affil=Department of Nuclear Medicine, University Hospital W?rzburg kn-affil= affil-num=3 en-affil=Comprehensive Heart Failure Center, University Hospital W?rzburg kn-affil= affil-num=4 en-affil=Department of Quantum Medical Technology, Graduate School of Medical Sciences kn-affil= affil-num=5 en-affil=Department of Quantum Medical Technology, Graduate School of Medical Sciences kn-affil= affil-num=6 en-affil=Nuclear Medicine, Medical Faculty, University of Augsburg kn-affil= affil-num=7 en-affil=Department of Diagnostic and Interventional Radiology, University Hospital W?rzburg kn-affil= affil-num=8 en-affil=Department of Nuclear Medicine, University Hospital W?rzburg kn-affil= affil-num=9 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Small-animal imaging kn-keyword=Small-animal imaging en-keyword=SPECT kn-keyword=SPECT en-keyword=Mouse kn-keyword=Mouse en-keyword=Collimator kn-keyword=Collimator en-keyword=Post-reconstruction filtering kn-keyword=Post-reconstruction filtering END start-ver=1.4 cd-journal=joma no-vol=10 cd-vols= no-issue=1 article-no= start-page=18616 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20201029 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Capabilities of multi-pinhole SPECT with two stationary detectors for in vivo rat imaging en-subtitle= kn-subtitle= en-abstract= kn-abstract=We aimed to investigate the image quality of the U-SPECT5/CT E-Class a micro single-photon emission computed tomography (SPECT) system with two large stationary detectors for visualization of rat hearts and bones using clinically available Tc-99m-labelled tracers. Sensitivity, spatial resolution, uniformity and contrast-to-noise ratio (CNR) of the small-animal SPECT scanner were investigated in phantom studies using an ultra-high-resolution rat and mouse multi-pinhole collimator (UHR-RM). Point source, hot-rod, and uniform phantoms with Tc-99m-solution were scanned for high-count performance assessment and count levels equal to animal scans, respectively. Reconstruction was performed using the similarity-regulated ordered-subsets expectation maximization (SROSEM) algorithm with Gaussian smoothing. Rats were injected with similar to 100 MBq [Tc-99m]Tc-MIBI or similar to 150 MBq [Tc-99m]Tc-HMDP and received multi-frame micro-SPECT imaging after tracer distribution. Animal scans were reconstructed for three different acquisition times and post-processed with different sized Gaussian filters. Following reconstruction, CNR was calculated and image quality evaluated by three independent readers on a five-point scale from 1="very poor" to 5="very good". Point source sensitivity was 567 cps/MBq and radioactive rods as small as 1.2 mm were resolved with the UHR-RM collimator. Collimator-dependent uniformity was 55.5%. Phantom CNR improved with increasing rod size, filter size and activity concentration. Left ventricle and bone structures were successfully visualized in rat experiments. Image quality was strongly affected by the extent of post-filtering, whereas scan time did not have substantial influence on visual assessment. Good image quality was achieved for resolution range greater than 1.8 mm in bone and 2.8 mm in heart. The recently introduced small animal SPECT system with two stationary detectors and UHR-RM collimator is capable to provide excellent image quality in heart and bone scans in a rat using standardized reconstruction parameters and appropriate post-filtering. However, there are still challenges in achieving maximum system resolution in the sub-millimeter range with in vivo settings under limited injection dose and acquisition time. en-copyright= kn-copyright= en-aut-name=JanssenJan P. en-aut-sei=Janssen en-aut-mei=Jan P. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HoffmannJan V. en-aut-sei=Hoffmann en-aut-mei=Jan V. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KannoTakayuki en-aut-sei=Kanno en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NoseNaoko en-aut-sei=Nose en-aut-mei=Naoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=GrunzJan-Peter en-aut-sei=Grunz en-aut-mei=Jan-Peter kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OnoguchiMasahisa en-aut-sei=Onoguchi en-aut-mei=Masahisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ChenXinyu en-aut-sei=Chen en-aut-mei=Xinyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=LapaConstantin en-aut-sei=Lapa en-aut-mei=Constantin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=BuckAndreas K. en-aut-sei=Buck en-aut-mei=Andreas K. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=HiguchiTakahiro en-aut-sei=Higuchi en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Nuclear Medicine, University Hospital W?rzburg kn-affil= affil-num=2 en-affil=Department of Nuclear Medicine, University Hospital W?rzburg kn-affil= affil-num=3 en-affil=Comprehensive Heart Failure Centre, University Hospital W?rzburg kn-affil= affil-num=4 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Diagnostic and Interventional Radiology, University Hospital W?rzburg kn-affil= affil-num=6 en-affil=Department of Quantum Medical Technology, Graduate School of Medical Sciences, Kanazawa University kn-affil= affil-num=7 en-affil=Comprehensive Heart Failure Centre, University Hospital W?rzburg kn-affil= affil-num=8 en-affil=Nuclear Medicine, Medical Faculty, University of Augsburg kn-affil= affil-num=9 en-affil=Department of Nuclear Medicine, University Hospital W?rzburg kn-affil= affil-num=10 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Biomarkers kn-keyword=Biomarkers en-keyword=Diagnostic markers kn-keyword=Diagnostic markers en-keyword=Medical research kn-keyword=Medical research en-keyword=Preclinical research kn-keyword=Preclinical research en-keyword=Translational research kn-keyword=Translational research END start-ver=1.4 cd-journal=joma no-vol=23 cd-vols= no-issue=4 article-no= start-page=100998 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200424 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cytotoxic T Lymphocytes Regenerated from iPS Cells Have Therapeutic Efficacy in a Patient-Derived Xenograft Solid Tumor Model en-subtitle= kn-subtitle= en-abstract= kn-abstract=Current adoptive T cell therapies conducted in an autologous setting are costly, time consuming, and depend on the quality of the patient's T cells. To address these issues, we developed a strategy in which cytotoxic T lymphocytes (CTLs) are regenerated from iPSCs that were originally derived from T cells and succeeded in regenerating CTLs specific for the WT1 antigen, which exhibited therapeutic efficacy in a xenograft model of leukemia. In this study, we extended our strategy to solid tumors. The regenerated WT1-specific CTLs had a strong therapeutic effect in orthotopic xenograft model using a renal cell carcinoma (RCC) cell line. To make our method more generally applicable, we developed an allogeneic approach by transducing HLA-haplotype homozygous iPSCs with WT1-specific TCR / genes that had been tested clinically. The regenerated CTLs antigen-specifically suppressed tumor growth in a patient-derived xenograft model of RCC, demonstrating the feasibility of our strategy against solid tumors. en-copyright= kn-copyright= en-aut-name=KashimaSoki en-aut-sei=Kashima en-aut-mei=Soki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MaedaTakuya en-aut-sei=Maeda en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MasudaKyoko en-aut-sei=Masuda en-aut-mei=Kyoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NaganoSeiji en-aut-sei=Nagano en-aut-mei=Seiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=InoueTakamitsu en-aut-sei=Inoue en-aut-mei=Takamitsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakedaMasashi en-aut-sei=Takeda en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KonoYuka en-aut-sei=Kono en-aut-mei=Yuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KobayashiTakashi en-aut-sei=Kobayashi en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SaitoShigeyoshi en-aut-sei=Saito en-aut-mei=Shigeyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=HiguchiTakahiro en-aut-sei=Higuchi en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=Ichise Hiroshi en-aut-sei=Ichise en-aut-mei= Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KobayashiYuka en-aut-sei=Kobayashi en-aut-mei=Yuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=IwaisakoKeiko en-aut-sei=Iwaisako en-aut-mei=Keiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=TeradaKoji en-aut-sei=Terada en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=AgataYasutoshi en-aut-sei=Agata en-aut-mei=Yasutoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=NumakuraKazuyuki en-aut-sei=Numakura en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=SaitoMitsuru en-aut-sei=Saito en-aut-mei=Mitsuru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=NaritaShintaro en-aut-sei=Narita en-aut-mei=Shintaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=YasukawaMasaki en-aut-sei=Yasukawa en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=OgawaOsamu en-aut-sei=Ogawa en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=HabuchiTomonori en-aut-sei=Habuchi en-aut-mei=Tomonori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=KawamotoHiroshi en-aut-sei=Kawamoto en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= affil-num=1 en-affil=Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University kn-affil= affil-num=2 en-affil=Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University kn-affil= affil-num=3 en-affil=Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University kn-affil= affil-num=4 en-affil=Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University kn-affil= affil-num=5 en-affil= Department of Urology, Akita University Graduate School of Medicine kn-affil= affil-num=6 en-affil=Department of Urology, Kyoto University Graduate School of Medicine kn-affil= affil-num=7 en-affil= Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University kn-affil= affil-num=8 en-affil=Department of Urology, Kyoto University Graduate School of Medicine kn-affil= affil-num=9 en-affil=Department of Medical Physics and Engineering, Division of Health Sciences, Osaka University kn-affil= affil-num=10 en-affil=Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=11 en-affil=Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University kn-affil= affil-num=12 en-affil=Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University kn-affil= affil-num=13 en-affil=Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University kn-affil= affil-num=14 en-affil=Department of Biochemistry and Molecular Biology, Shiga University of Medical School kn-affil= affil-num=15 en-affil=Department of Biochemistry and Molecular Biology, Shiga University of Medical School kn-affil= affil-num=16 en-affil=Department of Urology, Akita University Graduate School of Medicine kn-affil= affil-num=17 en-affil=Department of Urology, Akita University Graduate School of Medicine kn-affil= affil-num=18 en-affil=Department of Urology, Akita University Graduate School of Medicine kn-affil= affil-num=19 en-affil=Department of Hematology, Clinical Immunology and Infectious Diseases, Graduate School of Medicine, Ehime University kn-affil= affil-num=20 en-affil=Department of Urology, Kyoto University Graduate School of Medicine kn-affil= affil-num=21 en-affil=Department of Urology, Akita University Graduate School of Medicine kn-affil= affil-num=22 en-affil= Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University kn-affil= en-keyword=Cancer kn-keyword=Cancer en-keyword=Cellular Therapy kn-keyword=Cellular Therapy en-keyword=Immunological Methods kn-keyword=Immunological Methods END start-ver=1.4 cd-journal=joma no-vol=127 cd-vols= no-issue=6 article-no= start-page=851 end-page=873 dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200409 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements en-subtitle= kn-subtitle= en-abstract= kn-abstract=The norepinephrine transporter (NET) is a major target for the evaluation of the cardiac sympathetic nerve system in patients with heart failure and Parkinson's disease. It is also used in the therapeutic applications against certain types of neuroendocrine tumors, as exemplified by the clinically used 123/131I-MIBG as theranostic single-photon emission computed tomography (SPECT) agent. With the development of more advanced positron emission tomography (PET) technology, more radiotracers targeting NET have been reported, with superior temporal and spatial resolutions, along with the possibility of functional and kinetic analysis. More recently, fluorine-18-labelled NET tracers have drawn increasing attentions from researchers, due to their longer radiological half-life relative to carbon-11 (110 min vs. 20 min), reduced dependence on on-site cyclotrons, and flexibility in the design of novel tracer structures. In the heart, certain NET tracers provide integral diagnostic information on sympathetic innervation and the nerve status. In the central nervous system, such radiotracers can reveal NET distribution and density in pathological conditions. Most radiotracers targeting cardiac NET-function for the cardiac application consistent of derivatives of either norepinephrine or MIBG with its benzylguanidine core structure, e.g. 11C-HED and 18F-LMI1195. In contrast, all NET tracers used in central nervous system applications are derived from clinically used antidepressants. Lastly, possible applications of NET as selective tracers over organic cation transporters (OCTs) in the kidneys and other organs controlled by sympathetic nervous system will also be discussed. en-copyright= kn-copyright= en-aut-name=ChenXinyu en-aut-sei=Chen en-aut-mei=Xinyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KudoTakashi en-aut-sei=Kudo en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=LapaConstantin en-aut-sei=Lapa en-aut-mei=Constantin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=BuckAndreas en-aut-sei=Buck en-aut-mei=Andreas kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HiguchiTakahiro en-aut-sei=Higuchi en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Nuclear Medicine, University Hospital of W?rzburg kn-affil= affil-num=2 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Nuclear Medicine, University Hospital of W?rzburg kn-affil= affil-num=4 en-affil=Department of Nuclear Medicine, University Hospital of W?rzburg kn-affil= affil-num=5 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Norepinephrine transporter kn-keyword=Norepinephrine transporter en-keyword=Benzylguanidine kn-keyword=Benzylguanidine en-keyword=Phenethylguanidine kn-keyword=Phenethylguanidine en-keyword=Antidepressant kn-keyword=Antidepressant en-keyword=Organic cation transporter kn-keyword=Organic cation transporter END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue= article-no= start-page=17026 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20191119 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Ventricular Distribution Pattern of the Novel Sympathetic Nerve PET Radiotracer F-18-LMI1195 in Rabbit Hearts en-subtitle= kn-subtitle= en-abstract= kn-abstract=We aimed to determine a detailed regional ventricular distribution pattern of the novel cardiac nerve PET radiotracer F-18-LMI1195 in healthy rabbits. Ex-vivo high resolution autoradiographic imaging was conducted to identify accurate ventricular distribution of F-18-LMI1195. In healthy rabbits, F-18-LMI1195 was administered followed by the reference perfusion marker Tl-201 for a dual-radiotracer analysis. After 20 min of F-18-LMI1195 distribution time, the rabbits were euthanized, the hearts were extracted, frozen, and cut into 20-mu m short axis slices. Subsequently, the short axis sections were exposed to a phosphor imaging plate to determine F-18-LMI1195 distribution (exposure for 3 h). After complete F-18 decay, sections were re-exposed to determine Tl-201 distribution (exposure for 7 days). For quantitative analysis, segmental regions of Interest (ROIs) were divided into four left ventricular (LV) and a right ventricular (RV) segment on mid-ventricular short axis sections. Subendocardial, midportion, and subepicardial ROIs were placed on the LV lateral wall. F-18-LMI1195 distribution was almost homogeneous throughout the LV wall without any significant differences in all four LV ROIs (anterior, posterior, septal and lateral wall, 99 +/- 2, 94 +/- 5, 94 +/- 4 and 97 +/- 3%LV, respectively, n.s.). Subepicardial Tl-201 uptake was significantly lower compared to the subendocardial portion (subendocardial, midportion, and subepicardial activity: 90 +/- 3, 96 +/- 2 and *80 +/- 5%LV, respectively, *p < 0.01 vs. midportion). This was in contradistinction to the transmural wall profile of F-18-LMI1195 (90 +/- 4, 96 +/- 5 and 84 +/- 4%LV, n.s.). A slight but significant discrepant transmural radiotracer distribution pattern of Tl-201 in comparison to F-18-LMI1195 may be a reflection of physiological sympathetic innervation and perfusion in rabbit hearts. en-copyright= kn-copyright= en-aut-name=WernerRudolf A. en-aut-sei=Werner en-aut-mei=Rudolf A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WakabayashiHiroshi en-aut-sei=Wakabayashi en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ChenXinyu en-aut-sei=Chen en-aut-mei=Xinyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HayakawaNobuyuki en-aut-sei=Hayakawa en-aut-mei=Nobuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=LapaConstantin en-aut-sei=Lapa en-aut-mei=Constantin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=RoweSteven P. en-aut-sei=Rowe en-aut-mei=Steven P. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=JavadiMehrbod S. en-aut-sei=Javadi en-aut-mei=Mehrbod S. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=RobinsonSimon en-aut-sei=Robinson en-aut-mei=Simon kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HiguchiTakahiro en-aut-sei=Higuchi en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=The Russell H. Morgan Department of Radiology and Radiological Science, Division of Nuclear Medicine and Molecular Imaging, Johns Hopkins School University of Medicine kn-affil= affil-num=2 en-affil= Department of Nuclear Medicine, Hannover Medical School kn-affil= affil-num=3 en-affil= Department of Nuclear Medicine, Hannover Medical School kn-affil= affil-num=4 en-affil= Department of Nuclear Medicine, Hannover Medical School kn-affil= affil-num=5 en-affil=Department of Nuclear Medicine, University Hospital, University of W?rzburg kn-affil= affil-num=6 en-affil=The Russell H. Morgan Department of Radiology and Radiological Science, Division of Nuclear Medicine and Molecular Imaging, Johns Hopkins School University of Medicine kn-affil= affil-num=7 en-affil=The Russell H. Morgan Department of Radiology and Radiological Science, Division of Nuclear Medicine and Molecular Imaging, Johns Hopkins School University of Medicine kn-affil= affil-num=8 en-affil= Lantheus Medical Imaging kn-affil= affil-num=9 en-affil=Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= END start-ver=1.4 cd-journal=joma no-vol=22 cd-vols= no-issue=3 article-no= start-page=602 end-page=611 dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20190722 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Initial Evaluation of AF78: a Rationally Designed Fluorine-18-Labelled PET Radiotracer Targeting Norepinephrine Transporter en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose
Taking full advantage of positron emission tomography (PET) technology, fluorine-18-labelled radiotracers targeting norepinephrine transporter (NET) have potential applications in the diagnosis and assessment of cardiac sympathetic nerve conditions as well as the delineation of neuroendocrine tumours. However, to date, none have been used clinically. Drawbacks of currently reported radiotracers include suboptimal kinetics and challenging radiolabelling procedures.
Procedures
We developed a novel fluorine-18-labelled radiotracer targeting NET, AF78, with efficient one-step radiolabelling based on the phenethylguanidine structure. Radiosynthesis of AF78 was undertaken, followed by validation in cell uptake studies, autoradiography, and in vivo imaging in rats.
Results
[18F]AF78 was successfully synthesized with 27.9?}?3.1 % radiochemical yield, >?97 % radiochemical purity and >?53.8 GBq/mmol molar activity. Cell uptake studies demonstrated essentially identical affinity for NET as norepinephrine and meta-iodobenzylgaunidine. Both ex vivo autoradiography and in vivo imaging in rats showed homogeneous and specific cardiac uptake.
Conclusions
The new PET radiotracer [18F]AF78 demonstrated high affinity for NET and favourable biodistribution in rats. A structure-activity relationship between radiotracer structures and affinity for NET was revealed, which may serve as the basis for the further design of NET targeting radiotracers with favourable features. en-copyright= kn-copyright= en-aut-name=ChenXinyu en-aut-sei=Chen en-aut-mei=Xinyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FritzAlexander en-aut-sei=Fritz en-aut-mei=Alexander kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WernerRudolf A. en-aut-sei=Werner en-aut-mei=Rudolf A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NoseNaoko en-aut-sei=Nose en-aut-mei=Naoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YagiYusuke en-aut-sei=Yagi en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KimuraHiroyuki en-aut-sei=Kimura en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=RoweSteven P. en-aut-sei=Rowe en-aut-mei=Steven P. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KoshinoKazuhiro en-aut-sei=Koshino en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=DeckerMichael en-aut-sei=Decker en-aut-mei=Michael kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=HiguchiTakahiro en-aut-sei=Higuchi en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Nuclear Medicine, University Hospital of W?rzburg kn-affil= affil-num=2 en-affil=Institute of Pharmacy and Food Chemistry, University of W?rzburg kn-affil= affil-num=3 en-affil=Department of Nuclear Medicine, University Hospital of W?rzburg kn-affil= affil-num=4 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Sciences, Kyoto Pharmaceutical University kn-affil= affil-num=6 en-affil=Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Sciences, Kyoto Pharmaceutical University kn-affil= affil-num=7 en-affil=Division of Nuclear Medicine and Molecular Imaging, Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine kn-affil= affil-num=8 en-affil=Department of Systems and Informatics, Hokkaido Information University kn-affil= affil-num=9 en-affil=Institute of Pharmacy and Food Chemistry, University of W?rzburg kn-affil= affil-num=10 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Norepinephrine transporter kn-keyword=Norepinephrine transporter en-keyword=Positron emission tomography kn-keyword=Positron emission tomography en-keyword=Phenethylguanidine kn-keyword=Phenethylguanidine en-keyword=[18F]AF78 kn-keyword=[18F]AF78 END