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Journal of Labelled Compounds Radiopharmaceuticals
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Volume 62 | Supplement 1 | 2019 ISSN 0362-4803
The 23rd International Symposium on Radiopharmaceutical Sciences (ISRS 2019) Beijing, China, 26-31 May 2019
wileyonlinelibrary.com/journal/jlcr
wileyonlinelibrary.com/journal/jlcr
Editorial board EDITORS-IN-CHIEF R F Dannals
K M W Lawrie
Division of Nuclear Medicine The Johns Hopkins University 600 North Wolfe Street Nelson Bl-127Baltimore, Maryland 21287-0816, USA E-mail: [email protected]
Essex United Kingdom E-mail: [email protected]
LABELLED COMPOUNDS EDITOR FOR EUROPE V Derdau
RADIOPHARMA CEUTICALS EDITOR FOR ASIA, AUSTRALIA AND NEW ZEALAND M Kassiou
Medicinal Chemistry, Isotope Chemistry & Metabolite Synthesis Sanofi Industriepark Hoechst, G87665926 Frankfurt Germany E-mail: [email protected]
School of Chemistry University of Sydney NSW 2006 Sydney Australia E-mail: michael.kassiou@ sydney.edu.au
LABELLED COMPOUNDS EDITOR FOR NORTH AMERICA B D Maxwell Doylestown PA 18902, USA E-mail: [email protected]
REVIEW EDITOR F. Aigbirhio
RADIOPHARMACEUTICALS EDITOR Daniëlle Vugts VUMC, Dept Radiology & Nuclear Medicine Location Radionuclide Center 1081 HV Amsterdam, The Netherlands E-mail: [email protected]
Wolfson Brain Imaging Centre University of Cambridge Addenbrooke’s Hospital, Cambridge, CB2 2QQ, UK E-mail: [email protected]
EDITORIAL ADVISORY BOARD
C Anderson University of Pittsburgh Pittsburgh, USA G Antoni Uppsala University Uppsala, Sweden J Atzrodt R&D Sanofi Aventis Deutschland Frankfurt am Main, Germany S P Bew University of East Anglia Norwich, Norfolk, UK X Chen NBIB Bethesda, USA D Y Chi Sogang University Seoul, Korea B Cornelissen University of Oxford Oxford, UK F Dollé Service Hospitalier Frédéric Joliot Orsay, France C Elmore AstraZeneca Mölndal, Sweden
C N Filer Perkin Elmer Life Sciences Inc Boston, USA T Hartung Roche Basel, Switzerland D Hesk Merck Research Laboratories Rahway, USA J Holland University of Zurich Zurich, Switzerland J A Katzenellenbogen University of Illinois Urbana, USA W Kerr University of Strathclyde Glasgow, UK S Lapi University of Alabama Tuscaloosa, USA B Latli Boehringer Ingelheim Ridgefield, USA J Llop CICbiomaGUNE San Sebastian, Spain
W J S Lockley University of Surrey Guildford, UK N Long Imperial College London, UK D Muri Roche Basel, Switzerland D Papagiannopoulou Aristotle University Thessaloniki, Greece J Passchier Imanova London, UK T Ross Hannover Medical School Hannover, Germany H Saji Kyoto University Kyoto, Japan R Salter Johnson & Johnson Raritan, USA D Schenk Merck Rahway, USA
M Schou Astrazeneca London, UK S Stone-Elander Karolinska Pharmacy Stockholm, Sweden N Summerhill Pharmaron Cardiff, GB M L Thakur Thomas Jefferson University Philadelphia, USA N Vasdev CAMH Toronto, Canada M R Zalutsky Duke University Medical Center Durham, USA M Zanda University of Aberdeen Aberdeen, Scotland X Zhang Xiamen University Xiamen, China
wileyonlinelibrary.com/journal/jlcr
Aims and scope The Official Journal of the International Isotope Society The Journal of Labelled Compounds and Radiopharmaceuticals publishes original scientific manuscripts dealing with all aspects of research in labelled compound preparation and application. This includes areas such as analytical control, self radiolysis, quality control handling, storage, and tracer methods used in chemical, biochemical, biological, pharmacological, medical, genetic, agricultural and geochemical research. All radionuclides and enriched stable nuclides are included. The Journal of Labelled Compounds and Radiopharmaceuticals devotes particular attention to the following fields: radionuclide production; cyclotron targetry; neutron irradiation methodology; precursor preparation and production; labelling synthesis (chemical, biochemical, radiation, isotope exchange, etc); automation of nuclide production, precursor, preparation and synthesis; analysis (methods, limitations, etc. for both radioactive and stable nuclides, including new detection techniques); radiopharmaceuticals; PET chemistry; quality control (an essential requirement for valid data and especially for radiopharmaceuticals); stability and storage problems; handling of Curie and multiCurie amounts of radioactivity; etc. JLCR Award for Young Scientists: The Journal of Labelled Compounds and Radiopharmaceuticals, in cooperation with the International Isotope Society Conferences and the International Conferences on Radiopharmaceutical Sciences, sponsor every year four Awards to early excellence in radiopharmaceutical research and isotope labelling.
Copyright and copying (in any format) Copyright © 2019 John Wiley & Sons, Ltd. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means without the prior permission in writing from the copyright holder. Authorization to copy items for internal and personal use is granted by the copyright holder for libraries and other users registered with their local Reproduction Rights Organisation (RRO), e.g. Copyright Clearance Center (CCC), 222 Rosewood Drive, Danvers, MA 01923, USA (www.copyright.com), provided the appropriate fee is paid directly to the RRO. This consent does not extend to other kinds of copying such as copying for general distribution, for advertising or promotional purposes, for republication, for creating new collective works or for resale. Permissions for such reuse can be obtained using the RightsLink “Request Permissions” link on Wiley Online Library. Special requests should be addressed to: [email protected]
Disclaimer The Publisher and Editors cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed do not necessarily ref lect those of the Publisher and Editors, neither does the publication of advertisements constitute any endorsement by the Publisher and Editors of the products advertised.
wileyonlinelibrary.com/journal/jlcr
The 23rd International Symposium on Radiopharmaceutical Sciences
Beijing, China May 26th to May 31st, 2019
Sponsored by the Society of Radiopharmaceutical Sciences
Scientific Program Committee Members
Chen, Xiaoyuan, PhD
National Institutes of Health, Bethesda, MD, USA
Chin, Frederick T., PhD
Stanford University, Stanford, CA, USA
Cutler, Cathy, PhD
Brookhaven National Laboratory, Upton, NY, USA
Gee, Antony PhD
King’s College London, London, UK
Huclier, Sandrine, PhD
Subatech Laboratory, Nantes, France
Jeong, Jae Min, PhD
Seoul National University, Seoul, South Korea
Jia, Hongmei, PhD
Beijing Normal University, Beijing, China
Kuge, Yuji, PhD
Hokkaido University, Sapporo, Japan
Kung, Hank, PhD
University of Pennsylvania, Philadelphia, PA, USA
Wang, Fan, PhD (Chair)
Peking University, Beijing, China
Yang, Zhi, PhD
Peking University, Beijing, China
Local Arrangements Committee Members Fan Wang (Chair), Professor, Peking University Zuoxiang He, Professor, Fu Wai Hospital, Chinese Academy of Medical Sciences Jian Wu, General Manager, China Isotope and Radiation CorporaƟon Minhao Xie, Professor, Jiangsu Institute of Nuclear Medicine Xianzhong Zhang, Professor, Xiamen University Zhaofei Liu, Professor, Peking University Bing Jia, Associate Professor, Peking University Jiyun Shi, Associate Professor, Institute of Biophysics, Chinese Academy of Sciences
History of ISRS: List of Venues
23rd ISRS
May 26-31, 2019 – Beijing, China
22nd ISRS
May 14-19, 2017 – Dresden, Germany
21st ISRS
May 26 – 31, 2015 – Columbia, MO, USA
20th ISRS
May 12 – 17, 2013 – Jeju Island, South Korea
19th ISRS
August 28 – September 2, 2011 – Amsterdam, Netherlands
18th ISRS
July 12- 16, 2009 – Edmonton, AB, Canada
17th ISRS
April 30 – May 4, 2007 – Aachen, Germany
16th ISRC
June 20 – 24, 2005 – Iowa City, IA, USA
15th ISRC
August 10 – 14, 2003 – Sydney, Australia
14th ISRC
June 10 – 15, 2001 – Interlaken, Switzerland
13th ISRC
June 27 – July 1, 1999 – St. Louis, MO, USA
12th ISRC
June 15 – 19, 1997 – Uppsala, Sweden
11th ISRC
August 13 – 17, 1995 – Vancouver, BC, Canada
10th ISRC
October 25 – 28, 1993 – Kyoto, Japan
9th ISRS
April 6 – 10, 1992 – Paris, France
8th ISRS
June 24 – 29, 1990 – Princeton, NJ, USA
7th ISRS
July 4 – 8, 1988 – Groningen, Netherlands
6th ISRS
June 29 – July 3, 1986 – Boston, MA, USA
5th ISRC
July 9 – 13, 1984 – Tokyo, Japan
4th ISRC
August 23 – 27, 1982 – Jülich, Germany
3rd ISRC
June 16 – 20, 1980 – St. Louis, MO, USA
2nd ISRC
July 3 – 7, 1978 – Oxford, Great Britain
1st ISRC
September 21– 24, 1976 – Brookhaven, NY, USA
Abstract Reviewers Adam, Michael, Canada Alberto, Roger, Switzerland Ametamey, Simon, Switzerland Anderson, Carolyn, United States Antoni, Gunnar, Sweden Arstad, Erik, United Kingdom Avila-Rodriguez, Miguel, Mexico Barkhausen, Christoph, Germany Barre, Louisa, France Berroteran-Infante, Neydher, Austria Bhalla, Rajiv, Australia Bilewicz, Aleksander, Poland Blower, Phil, United Kingdom Bongarzone, Salvatore, United Kingdom Brechbiel, Martin, United States Brust, Peter, Germany Chan, James, Australia Chen, Xiaoyuan, United States Cheng, Zhen, United States Chi, Dae Yoon, Korea, Republic of Choe, Yearn Seong, Korea, Republic of Chun, Joong-Hyun, Korea, Republic of Clark, John, United Kingdom Coenen, Heinz, Germany Cui, Mengchao, China Cutler, Cathy, United States DeGrado, Timothy, United States Deri, Melissa, United States Dolleˊ, Freˊdeˊric, France Donnelly, Paul, Australia Eckelman, William, United States Ekoume, Fany, Cameroon Elsinga, Philip, Netherlands Francesconi, Lynn, United States Fuchigami, Takeshi, Japan Gagnon, Katie, Sweden Gee, Antony, United Kingdom Gott, Matthew, United States Halldin, Christer, Sweden Haskali, Mohammad, Australia Herth, Matthias, Sweden Hoepping, Alexander, Germany Holger, Stephan, Germany Horti, Andrew, United States Janssen, Bieneke, United States Jensen, Svend, Denmark Jeong, Jae Min, Korea, Republic of Jia, Hongmei, China Jia, Bing, China Jin, Hongjun, China Jurisson, Silvia, United States Kassiou, Michael, Australia Kilbourn, Michael, United States Kim, Hee-Kwon, Korea, Republic of
Kim, Dong Wook, Korea, Republic of Kirjavainen, Anna, Finland Kiyono, Yasushi, Japan Kniess, Torsten, Germany Kopka, Klaus, Germany Krasikova, Raisa, Russian Federation Krohn, Kenneth, United States Kubeil, Manja, Germany Kuge, Yuji, Japan Kuhnast, Bertrand, France Lapi, Suzanne, United States Larsen, Peter, Denmark Laube, Markus, Germany Lebeda, Ondrej, Czech Republic Lee, Kyo Chul, Korea, Republic of Lee, Byung Chul, Korea, Republic of Lee, Yun-Sang, Korea, Republic of Lever, Susan, United States Lewis, Jason, United States Lewis, Michael, United States Li, Zijing, China Liang, Steven, United States Link, Jeanne, United States Liu, Zhaofei, China Liu, Zhibo, China Loeser, Reik, Germany Ma, Michelle, United Kingdom Mach, Robert, United States Maina-Nock, Theodosia, Greece Mamat, Constan n, Germany Mathis, Chester, United States Meyer, Geerd, Germany Middel, Oskar, Norway Mikolajczak, Renata, Poland Mindt, Thomas, Austria Moldes-Amaya, Angel, Norway Mu, Linjing, Switzerland Mukherjee, Jogeshwar, United States Nagren, Kjell, Denmark Neels, Oliver, Germany Neumaier, Bernd, Germany Nickles, Robert, United States Ogawa, Kazuma, Japan Ogawa, Mikako, Japan Orvig, Chris, Canada Pandey, Mukesh, United States Papagiannopoulou, Dionysia, Greece Pascali, Claudio, Italy Pascali, Giancarlo, Australia Pichler, Verena, Austria Piel, Markus, Germany Pietzsch, Hans-Jürgen, Germany Pietzsch, Jens, Germany Pike, Victor, United States
Pillarsetty, Naga Vara Kishore, United States Poot, Alex, Netherlands Qaim, Syed, Germany Quinn, Thomas, United States Radchenko, Valery, Canada Ramogida, Caterina, Canada Reichert, David, United States Riss, Patrick, Norway Ross, Tobias, Germany Rotsch, David, United States Rotstein, Benjamin, Canada Rubow, Sietske, South Africa Samnick, Samuel, Germany Schultz, Michael, United States Scott, Peter, United States Signore, Alberto, Italy Spreckelmeyer, Sarah, Germany Stehouwer, Jeff, United States Steinbach, Jörg, Germany Toyohara, Jun, Japan Ueda, Masashi, Japan van Dam, R. Michael, United States van der Wildt, Berend, United States VanBrocklin, Henry, United States Verbruggen, Alfons, Belgium Vraka, Chrysoula, Austria Vugts, Danielle, Netherlands Wadsak, Wolfgang, Austria Wängler, Björn, Germany Wang, Mingwei, China Wang, Fan, China Wester, Hans-Juergen, Germany Windhorst, Albert, Netherlands Wuest, Frank, Canada Xin, Yangchun, United States Yang, Zhi, China Yang, Xing, China Yordanov, Alexander, United States Zhang, Ming-Rong, Japan Zhang, Jinming, China Zhang, Xianzhong, China Zhang, Junbo, China Zhu, Hua, China Baranski, Ann-Christin, Germany Decristoforo, Clemens, Austria Bolzati, Cristina, Italy Gillings, Nic, Denmark Solin, Olof, Finland Garg, Pradeep, United States Huclier, Sandrine, France Wichmann, Christian, Australia
Contents Orals
S6: Oral
23rd International Symposium on Radiopharmaceutical Sciences
KEYNOTE LECTURE 1 O-01
Pioneers require a spirit of determination and challenge: Milestones of PET radiopharmaceutical development T. Ido Neuroscience Research Institute, Gachon University, South Korea
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KEYNOTE LECTURE 2 O-02
Clinical translation of molecular imaging in nuclear medicine: PUMCH experience S 14 F. Li Peking Union Medical College Hospital, China; Beijing Key Laboratory of Molecular Imaging Diagnosis and Treatment of Nuclear Medicine, China; China Association of Nuclear Medicine Equipment, China; Chinese Journal of Nuclear Medicine and Molecular Imaging, China
RADIOLABELED COMPOUNDS - ONCOLOGY (IMAGING) SESSION 1 O-03
O-04
O-05
O-06
Bispecific anti-GRPR/PSMA heterodimer for PET and SPECT imaging diagnostic of prostate cancer A. Orlova1, B. Mitran1, Z. Varasteh1, A. Abouzayed1, S. Rinne1, M. Larhed2, V. Tolmachev1, U. Rosenström1 1Uppsala University, Sweden; 2Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Sweden Pretargeted tumor imaging with 64Cu-labeled ultrastable cross-bridged macrocyclic complex A. Bhise1, S. Sarkar2, P. Huynh2, W. Lee2, J. Y. Kim3, K. C. Lee4, J. Yoo1 1Kyungpook National University, Republic of Korea; 2Department of Molecular Medicine, Kyungpook National University, Republic of Korea; 3KIRAMS(Korea Institue of Radiological and Medical Sciences), Republic of Korea; 4KIRAMS, Republic of Korea Targeting CD206+ tumor-associated macrophages using a finely tuned albumin nano-platform for earlier detection of breast cancer metastases Ji Yong Park1, H. Chung2, K. Kim1, M. Suh1, S. H. Seok2, Y. Lee3 1Seoul National University, College of Medicine, Republic of Korea; 2Seoul National University, Republic of Korea; 3Seoul National University Hospital, Republic of Korea Improving pharmacokinetics of 99mTc-ref with PEG linkers for HER2-targeted SPECT imaging of breast cancer S. Du1, H. Gao1, C. Luo1, G. Yang1, Q. Luo2, B. Jia1, J. Shi3, F. Wang1,2 1Peking University, China; 2Institute of Biophysics, CAS, China; 3Institute of Biophysics, CAS, China
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RADIOCHEMISTRY - 18F SESSION 1 O-07
O-08
O-09
O-10
O-11
O-12
Generation of 18F-metal fluorides from [18F]HF generated by acidic QMA elution and application towards 18F-fluorination/ring-opening of complex epoxides S. Verhoog1, A. Brooks2, W. Winton2, A. Mossine2, M. Sanford2, P. Scott3 1Merck & Co Inc, USA; 2University of Michigan, USA; 3The University of Michigan, USA Pretargeted PET imaging using a dual click 18F-labeling strategy J. Steen1, C. Denk2, J. Jørgensen3, K. Nørregard3, R. Rossin5, M. Wilkovitsch2, D. Svatunek2, P. Edem6, C. Kuntner4, T. Wanek4, M. Robillard5, J. Kristensen6, A. Kjær3, H. Mikula2, M. Herth7 1Department of Drug Design and Pharmacology, University of Copenhagen, Denmark; 2Institute of Applied Synthetic Chemistry, Technische Universität Wien (TU Wien), Austria; 3Cluster for Molecular Imaging, Department of Biomedical Sciences, University of Copenhagen, Denmark; 4Health and Environment Department, Biomedical Systems, Austrian Institute of Technology (AIT), Austria; 5Tagworks Pharmaceuticals, Netherlands; 6Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; 7Univesity of Copenhagen, Sweden Development of high affinity 18F-labelled radiotracers for PET imaging of the adenosine A2A receptor T. H. Lai1, S. Schroeder1, F. Ludwig2, S. Fischer3, R. Moldovan4, M. Scheunemann1, S. Dukic-Stefanovic1, W. Deuther-Conrad1, J. Steinbach1, P. Brust1 1Helmholtz-Zentrum Dresden-Rossendorf, Germany; 2Department of Neuroradiopharmaceuticals, Institute for Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Germany; 3HZDR, FS Leipzig, Germany; 4Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden Rossendorf, Germany Preparation of [18F]fluoroalkenyliodonium salts and their application for radiolabeling by cross-coupling reactions S. Humpert1, M. Holschbach2, D. Bier3, B. Zlatopolskiy4, B. Neumaier1 1Forschungszentrum Jülich GmbH, Germany; 2Foschungszentrum Jülich GmbH, Germany; 3Forschungszentrum Juelich, Germany; 4Institute of Radiochemistry and Experimental Molecular Imaging (IREMB), University Hospital of Cologne, Germany High molar activity [18F]trifluoromethane for PET tracer synthesis A. Pees1, M. Vosjan2, V. Tadino3, J. Y. Chai4, H. Cha4, D. Y. Chi4, A. Windhorst5, D. Vugts1 1Amsterdam UMC, VU University, Netherlands; 2BV Cyclotron VU, Netherlands; 3ORA Neptis, Belgium; 4Department of Chemistry, Sogang University, Republic of Korea; 5VU University Medical Center, Netherlands Synthesis and evaluation of [18F]canagliflozin for imaging SGLT-2-transporters in diabetic patients K. Attia, T. Visser, J. Steven, R. Slart, I. Antunes, S. van der Hoek, P. Elsinga, H. Heerspink University Medical Center Groningen, Netherlands
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J Label Compd Radiopharm 2019: 62 (Suppl. 1): S5–S122
23rd International Symposium on Radiopharmaceutical Sciences
Oral: S7
MULTIMODALITY IMAGING PROBES/NANOPARTICLES O-13
O-14
O-15
O-16
Magnetic nanotheranostics enhances Cherenkov radiation–induced photodynamic therapy D. Ni1, D. Jiang1, W. Wei2, L. Kang3, J. Engle4, W. Cai1 1University of Wisconsin-Madison, USA; 2Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, China; 3Peking University First Hospital, China; 4Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA Bimodal PSMA ligands for intra-operative tumor detection and targeted photodynamic therapy of PSMA-expressing tumors Y. Derks1, H. Amatdjais2, J. Malekzad2, G. Franssen1, A. Kip1, D. Lowik2, O. Boerman1, M. Rijpkema1, P. Laverman1, S. Lutje1, S. Heskamp1 1Radboud University Medical Center, Netherlands; 2Radboud University, Netherlands Evaluation of N-alkylaminoferrocenes for in-vivo imaging of reactive oxygen species activity using PET and optical imaging J. Toms1, S. Maschauer1, S. Daum2, V. Reshetnikov2, A. Mokhir2, O. Prante1 1Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany; 2Department of Chemistry and Pharmacy, Organic Chemistry II, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany A Cell surface thiol targeting dual PET and fluorescent labelling reagent for multi-scale cell tracking T. Pham1, R. Yan, J. Maher King’s College London, UK
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RADIOCHEMISTRY - RADIOMETALS O-17
O-18
O-19
O-20
O-21
O-22
Towards cancer theranostics: 68Ga-, 44gSc-, 177Lu-, and 225Ac-labeled bombesin derivatives S. Ferguson1, M. Wuest1, C. Bergman1, N. Thiele2, S. Richter1, H. Jans1, V. Radchenko3, P. Causey4, R. Perron4, P. Schaffer3, J. Wilson2, T. Riauka1, F. Wuest1 1University of Alberta, Canada; 2Cornell University, USA; 3TRIUMF, Canada; 4Canadian Nuclear Laboratories (CNL), Canada Synthesis and comparison of novel fusarinine C-based chelators for 89Zr-labeling C. Zhai1, S. He2, X. Chen3, J. Lu3, C. Rangger4, D. Summer, H. Haas5, J. Foster6, J. Sosabowski7, C. Decristoforo8 1Southern Medical University, China; 2Department of Nuclear Medicine, Guangdong General Hospital, China; 3School of Forensic Medicine, Southern Medical University, China; 4Department of Nuclear Medicine, Medical University Innsbruck, Austria; 5Division of Molecular Biology, Biocenter, Medical University Innsbruck, Austria; 6Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, UK; 7Centre for Molecular Oncology and Imaging, UK; 8Medical University Innsbruck, Austria New bifunctional chelators for theranostic applications L. L. Li1, M. Jaraquemada-Pelaez2, N. Sarden2, H. Kuo3, E. A. Sarduy4, A. Robertson5, T. Kostelnik2, U. Jermilova2, E. Ehlerding4, H. Merkens6, K. Gitschtaler6, V. Radchenko7, K. Lin3, F. Benard3, J. Engle4, P. Schaffer7, C. Orvig1 1The University of British Columbia, Canada; 2Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, Vancouver, BC, Canada; 3BC Cancer Research Centre, Canada; 4Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 5Life Sciences Division, TRIUMF, Vancouver, BC, Canada; 6Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada; 7TRIUMF, Canada Cooperative capture synthesis for the development of novel supramolecular radiotracers F. d’Orchymont, J. Holland Department of Chemistry, University of Zurich, Switzerland In vivo stable bisarylmercury bispidine as a tool for Hg-197(m) applications I. M. Gilpin1, M. Walther2, J. Pietzsch3, H. Pietzsch2 1HZDR, Germany; 2Helmholtz-Zentrum Dresden-Rossendorf, Germany; 3Department Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Germany Positron emission tomography imaging of adeno-associated virus serotype 9-tetracystein (AAV9-TC) labeled with a multichelator J. W. Seo1, L. Mahakian2, E. Ingham2, S. Tumbale3, S. Shams2, E. Silva2, K. Ferrara2 1Stanford University, USA; 2Biomedical Engineering, UC Davis, USA; 3Radiology, Stanford, USA
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KEYNOTE LECTURE 3 O-23
Catalyzing the development and use of radiopharmaceuticals with total-body PET S. Cherry UC Davis
S 41
WILEY AWARD SESSION O-24
O-25
11C-Trifluoromethylation of primary aromatic amines with [11C]CuCF via diazonium salts generated in situ 3 N. Young1, C. Taddei, V. Pike National Institute of Mental Health, USA A long-acting radiolabeled RGD analogue 177Lu-AB-3PRGD2 for targeted radiotherapy of tumor H. Gao1, G. Yang1, C. Luo1, B. Jia1, J. Shi2, F. Wang1 1Peking University, China; 2Institute of Biophysics, CAS, China
J Label Compd Radiopharm 2019: 62 (Suppl. 1): S5–S122
S 42
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S8: Oral
O-26
O-27
23rd International Symposium on Radiopharmaceutical Sciences
Development of a radiation detector for miniaturized analysis of radiopharmaceutical samples via microchip electrophoresis J. Jones1, N. Ha2, R. M. van Dam3 1UCLA, USA; 2Lawrence Berkeley National Laboratory, USA; 3Crump Institute for Molecular Imaging, UCLA, USA Develop a peptide-based PET radiotracer for imaging PD-L1 expression in cancer K. Hu1, M. Zhang2, M. Hanyu3, L. Xie3, Y. Zhang4 1National Institute of Radiological Sciences, Japan; 2Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Japan; 3National Institute of Radiological Sciences (NIRS), National Institutes for Quantum and Radiological Science and Technology (QST), Japan; 4Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Japan
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RADIOCHEMISTRY - 11C AND OTHER POSITRON EMITTERS O-28
O-29
O-30
O-31
O-32
O-33
In-loop carbonylation-a novel and simplified method for carbon-11 labeling of drugs and radioligands M. Ferrat2, Y. E. Khoury2, K. Dahl1, C. Halldin2, M. Schou3 1CAMH and University of Toronto, Canada; 2Karolinska Institutet, Sweden; 3AstraZeneca PET Centre at Karolinska Institutet, Sweden Palladium/copper-mediated rapid 11C-cyanation of (hetero)arylstannanes Z. Zhang1, T. Niwa, Y. Watanabe, T. Hosoya RIKEN Center for Biosystems Dynamics Research, Japan Rapid, one-pot radiosynthesis of [carbonyl-11C]formamides from primary amines and [11C]CO2 F. Luzi1, S. Bongarzone, A. Gee King’s College London, UK Radiosynthesis of carbon-11 labeled acylsulfonamides using [11C]CO carbonylation chemistry B. van der Wildt, B. Shen, F. Chin Stanford University, USA Synthesis of radiolabeled [11C]formamides: A new carbon-11 labeled building block to access novel PET tracers C. Bonnemaire1, J. Collet2, E. Ruijter3, R. Orru3, A. Windhorst4, D. Vugts5 1UMC Amsterdam, Netherlands; 2Department of Radiology and Nuclear Medicine, Netherlands; 3Vrije Universiteit Amsterdam, Netherlands; 4VU University Medical Center, Netherlands; 5Amsterdam UMC, VU University, Netherlands Rapid and efficient BEMP-mediated synthesis of 11C-labelled benzimidazolones using [11C]carbon dioxide K. Horkka1, K. Dahl2, C. Halldin1, M. Schou3 1Karolinska Institutet, Sweden; 2CAMH and University of Toronto, Canada; 3AstraZeneca PET Centre, Karolinska Institutet, Sweden
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RADIOLABELED COMPOUNDS - OTHER MEDICAL DISCIPLINES AND RADIOPHARMACOLOGY AND CARDIOLOGY O-34
O-35
O-36
O-37
[11C]Metoclopramide as a PET tracer to visualize ABCB1 induction at the mouse blood-brain-barrier S. Mairinger1, V. Zoufal2, T. Wanek3, M. Brackhan4, J. Stanek2, T. Filip2, M. Sauberer2, N. Tournier5, J. Pahnke4, O. Langer2 1Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Austria; 2AIT Austrian Institute of Technology GmbH, Austria; 3Health and Environment Department, Biomedical Systems, Austrian Institute of Technology (AIT), Austria; 4Department of Neuro-/Pathology, University of Oslo (UiO) and Oslo University Hospital (OUS), Norway; 5CEA, France A novel high-throughput cassette microdosing approach to screen PET imaging agents M. Sun1, H. Xiao2, H. Hong1, A. Zhang3, Y. Zhang1, Y. Liu2, L. Zhu4, H. Kung5, J. Qiao1 1College of Chemistry, Beijing Normal University, China; 2Beijing Institute of Brain Disorders, Capital Medical University, China; 3Collage of Chemistry, Beijing Normal University, China; 4Beijing Normal University, China; 5University of Pennsylvania, USA Synthesis and in vivo evaluation of a novel 18F-labelled PET tracer 18F-BBR for myocardial perfusion imaging in mice X. Wu1 , M. Liang2, R. Wang2, H. Cai2, Y. Chen2, C. Fan1 1Sichuan University, China; 2The Affiliated Hospital of Southwest Medical University, China Exclusive kidney accumulation of DNA origami nanostructures protects kidneys from acute injury D. Jiang1, D. Ni1, W. Wei2, L. Kang3, J. Engle4, W. Cai1 1University of Wisconsin-Madison, USA; 2Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, China; 3Peking University First Hospital, China; 4Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA
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RADIOLABELED COMPOUNDS - ONCOLOGY (IMAGING) SESSION 2 O-38
Development of the first 18F-labeled MCT1/MCT4 lactate transport inhibitor: Radiosynthesis and preliminary in vivo evaluation in mice M. Sadeghzadeh1, R. Moldovan2, B. Wenzel1, M. Kranz1, W. Deuther-Conrad1, M. Toussaint1, S. Fischer3, F. Ludwig4, R. Teodoro2, S. Jonnalagadda5, S. Jonnalagadda5, L. Drewes5, P. Brust1 1Helmholtz-Zentrum Dresden-Rossendorf, Germany; 2Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden Rossendorf, Germany; 3HZDR, FS Leipzig, Germany; 4Department of Neuroradiopharmaceuticals, Institute for Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Germany; 5University of Minnesota Duluth, USA
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Preclinical evaluation of 99mTc-labeled anti-EpCAM nanobody conjugates for imaging EpCAM receptor expression by immuno-SPECT T. Liu1, Y. Wu1, L. Shi2, Y. Wang3, H. Gao4, B. Hu4, X. Zhang2, H. Zhao1, Y. Wan5, B. Jia4, F. Wang4 1Medical Isotopes Research Center and Department of Radiation Medicine, Peking University, China; 2Medical Isotopes Research Center and Department of Radiation Medicine, China; 3Medical Isotopes Research Center, Peking University, China; 4Peking University, China; 5CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, China PET imaging of human melanoma using a novel 18F-labeled dual AmBF3 derivative of alpha-melanocyte stimulating hormone C. Zhang1, Z. Zhang1, K. Lin1, H. Merkens2, J. Zeisler1, N. Colpo1, D. Perrin3, F. Benard1 1BC Cancer Research Centre, Canada; 2Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada; 3Department of Chemistry, University of British Columbia, Canada Imaging of in vivo tumor senescence with a novel beta-galactosidase specific PET tracer J. Cotton1, B. Zhou1, J. Schwenck2, K. Wolter3, A. Kuehn4, K. Fuchs4, G. Reischl5, A. Maurer1, C. la Fougère2, L. Zender6, M. Krueger1, B. Pichler4 1Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University of Tübingen, Germany; 2Department of Nuclear Medicine and Clinical Molecular Imaging, Eberhard Karls University of Tübingen, Germany; 3Department of Physiology I, Institute of Physiology, Eberhard Karls University of Tübingen, Germany; 4Werner Siemens Imaging Center, Germany; 5University Hospital Tübingen, Germany; 6Department of Internal Medicine VIII, University Hospital Tübingen, Germany The in vivo and in vitro validation of two activin-receptor like kinase 5 targeting PET tracers L. Rotteveel1, A. Poot2, P. Dijke3, H. J. Bogaard4, A. Lammertsma4, A. Windhorst5 1Radiology and Nuclear Medicine, Radionuclide Center, Amsterdam UMC, VU University, Amsterdam, The Netherlands; 2Amsterdam UMC, VU University, Netherlands; 3Department of Molecular Cell Biology, Leiden University Medical Centre, Netherlands; 4Amsterdam UMC, VUmc, Netherlands; 5VU University Medical Center, Netherlands Molecular imaging of autotaxin: Targeting the crossroad of inflammation and cancer M. Litchfield1, M. Wuest1, E. Briard2, Y. Auberson3, T. McMullen1, D. Brindley1, F. Wuest1 1University of Alberta, Canada; 2Novartis Pharma AG, Switzerland; 3Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Switzerland
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Engineered antibodies—New possibilities for brain PET S. Syvanen Uppsala University, Sweden
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Toward Auger radiotherapy with rhodium-103m: Bifunctional 16aneS4 chelator synthesis and development of a rhodium-103m generator C. Magnus1, G. Severin2, F. Zhuravlev3, U. Köster4, J. Fonslet3, M. Jensen3, A. Jensen1 1DTU Nutech, Technical University of Denmark (DTU), Denmark; 2Technical University of Denmark, Denmark; 3Center for Nuclear Technologies, Technical University of Denmark, Denmark; 4Institut Laue-Langevin, France Synthesis of precursors for 211At-labelling of anti-PSMA HuJ591 mAb and stability comparison after in vitro cellular internalization A. Roumesy1, S. Gouard1, L. Navarro1, F. Lelan1, F. Haddad2, F. Guérard3, A. Faivre-Chauvet, M. Chérel4, J. Gestin4 1CRCINA, France; 2GIP ARRONAX, France; 3CRCINA, Inserm, CNRS, Nuclear Oncology Group, France; 4CRCINA, Inserm, CNRS, France Radiosynthesis of a novel 77Br-labeled PARP-1 inhibitor through Cu-mediated aryl boronic ester bromination P. Ellison1, J. Burkemper2, A. Olson3, S. Hoffman1, S. Reilly4, M. Makvandi4, R. Mach5, T. Barnhart1, S. Lapi6, J. Engle7 1University of Wisconsin, USA; 2Department of Radiology, University of Alabama, Birmingham School of Medicine, USA; 3Department of Medical Physics, University of Wisconsin, USA; 4Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, University of Pennsylvania, Perelman School of Medicine, USA; 5University of Pennsylvania, USA; 6University of Alabama at Birmingham, USA; 7Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA Large-scale production and isolation of theranostic radionuclides 76Br and 77Br P. Ellison1, A. Olson2, S. Hoffman1, T. Barnhart1, R. Nickles3, J. Engle4 1University of Wisconsin, USA; 2Department of Medical Physics, University of Wisconsin, USA; 3University of Wisconsin Medical Physics, USA; 4Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA
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Neuroinflammation imaging with the P2X7R PET tracer [11C]SMW139 in the experimental autoimmune encephalomyelitis (EAE) model W. Beaino1 , B. Janssen2, E. Kooijman3, R. Vos3, R. Schuit3, M. Kassiou4, D. Vugts3, H. de Vries3, A. Windhorst5 1Radiology and Nuclear Medicine, Radionuclide Center, Amsterdam UMC, VU University, Amsterdam, The Netherlands; 2University of Pennsylvania, USA; 3Amsterdam UMC, VU University, Netherlands; 4The University of Sydney, Australia; 5VU University Medical Center, Netherlands
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Fluorinated benzimidazole sulfones as candidate radioligands for CB2 PET-imaging A. Kallinen1, R. Boyd2, S. Lane1, R. Bhalla2, K. Mardon2, D. Stimson3, G. Cowin2, F. Nasrallah2, E. Werry1, M. Connor2, M. Kassiou1 1The University of Sydney, Australia; 2University of Queensland, Australia; 3Royal Prince Alfred Hospital, Australia Synthesis and evaluation in rats of [11C]NR2B-Me as a PET radioligand for NR2B subunits in NMDA receptors L. Cai1, J. Liow2, C. Morse2, R. Davies4, M. Frankland3, S. Zoghbi3, R. Innis1, V. Pike1 National Institute of Mental Health, USA; 2NIH, USA; 3NIMH, USA; 4Oberlin College, USA Evaluation of a novel iodine-125 ligand for efficient α-synuclein compound screening B. Janssen1, Z. Lengyel2, C. Hsieh1, J. Ferrie1, A. Riad1, K. Xu1, C. Weng3, E. J. Petersson1, R. Mach1 1University of Pennsylvania, USA; 2University of Pennsylvania School of Medicine, USA; 3Department of Radiology, University of Pennsylvania, USA Synthesis of [18F]fluorotetrazines and coupling to trans-cyclooctene functionalized antibodies for amyloid-beta PET J. Rokka1, X. Fang2, G. Hultqvist1, R. Faresjö1, D. Olberg3, G. Antoni4, L. Lannfelt5, D. Sehlin5, S. Syvanen5, J. Eriksson5 1Uppsala University, Sweden; 2Yale University, USA; 3Norsk medisinsk syklotronsenter AS/University of Oslo, Norway; 4Uppsala University Hospital, Sweden; 5Uppsala University Hospital and Department of Medicinal Chemistry, Uppsala University, Sweden Automated routine implementation of [11C]ITDM for a longitudinal evaluation of mGluR1 availability in the Q175DN mouse model for Huntington’s disease Špela Korat1, D. Bertoglio1, K. Cybulska1, J. Verhaeghe1, A. Miranda1, L. Mrzljak2, J. Bard2, C. Dominguez2, L. Liu2, I. Munoz-Sanjuan2, S. Stroobants3, L. Wyffels1, S. Staelens1 1Molecular Imaging Center Antwerp, University of Antwerp, Belgium; 2CHDI Foundation, USA; 1Antwerp University Hospital, Belgium
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Development of radiopharmaceutical; from bench to FDA approved clinical application H. F. Kung Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA; Five Eleven Pharma Inc, Philadelphia, PA, USA
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High-throughput radio-TLC using Cerenkov luminescence imaging J. Wang1, A. Rios1, K. Lisova1, R. Slavik2, A. F. Chatziioannou2, R. M. van Dam2 1UCLA, USA; 2Crump Institute for Molecular Imaging, UCLA, USA Rapid, inexpensive, and high-yielding radiosynthesis of 68Ga-PSMA using a versatile microfluidic device for prostate cancer PET imaging X. Zhang1, M. Nickels, F. Liu, L. Bellan, H. Manning Vanderbilt University, USA Automated radiosynthesis of [18F]atorvastatin via Ru-mediated 18F-deoxyfluorination: A prospective PET imaging tool for the assessment of statin related mechanisms of action G. Clemente1, J. Rickmeier2, T. Zarganes-Tzitzikas3, I. Antunes4, R. Slart3, A. Dömling3, T. Ritter2, P. Elsinga1 1University Medical Center Groningen, Netherlands; 2Max-Planck-Institut für Kohlenforschung, Germany; 3Department of Drug Design, University of Groningen, Netherlands; 4UMCG, Netherlands Online positron detector for LC/MS/MS A. Kirjavainen1, S. Lahdenpohja1, S. Forsback2, O. Solin2 1Turku PET Center, University of Turku, Finland; 2University of Turku, Finland
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Radiosynthetic optimization of the SV2A radiotracer 18F-SDM-8: A search for the best precursor X. Wu1, S. Li2, M. Zheng3, Y. Huang4 1Sichuan University, China; 2Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, USA; 3Yale University School of Medicine, USA; 4PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, USA Discovery and first-in-human evaluation of M4 PAM PET tracer [11C]MK-6884 W. Li1 , Y. Wang, Z. Zeng1, T. Lohith1, L. Tong1, R. Mazzola1, K. Riffel2, P. Miller1, M. Purcell1, M. Holahan1, H. Haley1, L. Gantert1, J. Morrow1, T. Bueters1, J. Uslaner1, J. de Hoon3, G. Bormans4, M. Koole4, K. Laere4, K. Serdons4, R. Declercq5, I. Lepeleire5, M. Rudd1, D. Tellers1, A. Basile1, E. Hostetler1 1Merck Research Laboratories, USA; 2Merck & Co, Inc, USA; 3University Hospital Leuven, Belgium; 4KU Leuven, Belgium; 5Merck Sharp & Dohme (Europe) Inc, Belgium An 18F-labeled radiotracer for PET imaging of 11β-HSD1: From chemistry development to clinical study S. Li1, S. Bhatt1, D. Matuskey2, D. Holden1, W. Zhang3, Z. Cai2, N. Nabulsi4, Y. Ye1, H. Gao2, M. Kapinos2, R. Carson1, S. McKee5, K. Cosgrove5, A. Hillmer1, Y. Huang2 1Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, USA; 2PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, USA; 3Department of Nuclear Medicine, West China Hospital, Sichuan University, China; 4Yale PET Center, USA; 5Department of Psychiatry, Yale University, USA
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Structure-activity relationship studies of pyridine-based ligands and identification of a fluorinated derivative for the PET imaging of cannabinoid type 2 receptors A. Haider4, J. Kretz, L. Gobbi1, U. Grether2, C. Ullmer2, M. Honer2, I. Knuesel2, A. M. Herde4, M. Weber2, A. Brink2, C. Keller3, R. Schibli3, L. Mu3, S. Ametamey4 1F. Hoffmann - La Roche, Switzerland; 2Hoffmann-La Roche Ltd, Switzerland; 3ETH Zurich, Switzerland; 4Radiopharmacy, ETH Zurich, Switzerland; 5Kantonsspital St. Galen, Switzerland Synthesis and evaluation of 18F-labeled benzimidazopyridine derivatives as novel PET tracers for tau imaging H. Watanabe1, S. Kaide1, Y. Tarumizu1, Y. Shimizu2, S. Iikuni3, M. Ono3 1Graduate School of Pharmaceutical Sciences, Kyoto University, Japan; 2Graduate School of Medicine, Kyoto University, Kyoto, Japan; 3Kyoto University, Japan Development of a carbon-11 PET pro-radiotracer for imaging the astroglial excitatory amino acid transporter 2 I. Fontana2, E. Zimmer1, D. Souza1, S. Bongarzone2, A. Gee2 1Universidade Federal do Rio Grande do Sul, Brazil; 2King’s College London, United Kingdom
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Comparison of Al18F and 68Ga-labeled NOTA-PEG4-LLP2A for PET imaging of very late antigen-4 in melanoma Y. Gai1, L. Yuan, H. Li, X. Lan Department of Nuclear Medicine, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China 18F-labelled click based PSMA-tracer for prostate cancer imaging V. Bohmer1, D. van der Born2, W. Szymanski3, I. Antunes3, M. Klopstra4, D. Samplonius1, J. Sijbesma1, W. Helfrich1, T. Visser4, B. Feringa1, P. Elsinga1 1University Medical Center Groningen, Netherlands; 2FutureChemistry Holding B.V., Netherlands; 3UMCG, Netherlands; 4Syncom, Netherlands Preclinical evaluation of [18F]DiFA, a novel hypoxia PET probe, in a rat intracranial glioma model H. Yasui1, K. Higashikawa1, Y. Shibata2, H. Matsumoto3, T. Shiga4, N. Tamaki5, Y. Kuge1 1Hokkaido University, Japan; 2Graduate School of Biomedical Science and Engineering, Hokkaido University, Japan; 3Nihon Medi-Physics Co, Ltd, Japan; 4Graduate School of Medicine, Hokkaido University, Japan; 5Department of Radiology, Kyoto Prefectural University of Medicine, Japan Dynamic PET/CT imaging of 18F-(2S, 4R)4-fluoroglutamine in breast cancer patients X. Xu1,2,3,4,5, H. Zhu1,2,3,4,5, Z. Yang1,2,3,4,5 Hokkaido University, Japan; 2Graduate School of Biomedical Science and Engineering, Hokkaido University, Japan; 3Nihon Medi-Physics Co, Ltd, Japan; 4Graduate School of Medicine, Hokkaido University, Japan; 5Department of Radiology, Kyoto Prefectural University of Medicine, Japan
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Dual radionuclide theranostic pretargeting O. Keinanen1, R. Membreno, K. Fung, B. Zeglis Hunter College, USA [68Ga]/[177Lu]P17-087: A potential theranostic agent targeting PSMA expressing tumor H. Kung1, S. R. Choi2, Z. Zha1, K. Ploessl1, D. Alexoff3 1University of Pennsylvania, USA; 2Five Eleven Pharma, USA; 3Five Eleven Pharma Inc, USA Selection of the optimal macrocyclic chelators for labelling with 111In and 68Ga improves contrast of HER2 imaging using engineered scaffold protein ADAPT6 V. Tolmachev1, S. Lindbo2, M. Altai1, E. von Witting2, A. Vorobyeva1, M. Oroujeni1, B. Mitran1, A. Orlova1, J. Garousi1, S. Hober2 1Uppsala University, Sweden; 2KTH, Royal Institute of Technology, Sweden A Metabolically stable boron-derived tyrosine serves as a theranostic agent for positron emission tomography guided boron neutron capture therapy J. Li1, Y. Shi, Z. Zhang2, T. Liu2, X. Chen3, Z. Liu1 1Peking University, China; 2Beijing Capture Tech (BCTC), China; 3NIBIB/CC/NIH, USA Barium ferrite magnetic nanoparticles labeled with 223Ra: A new potential magnetic radiobioconjugate for targeted alpha therapy A. Bilewicz1, E. Cedrowska1, W. Gawęda1, F. Bruchertseifer, A. Morgenstern2 1Instutute of Nuclear Chemistry and Technology, Poland; 2Institute for Transuranium Elements, Germany Photodynamic therapy with a CD276-targeted agent for enhancing tumor anti-PD-1/PD-L1 immune checkpoint inhibition B. Rui1 , Y. Wang2, L. Jianhao1, Z. Liu3, F. Wang3 1Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, China; 2Medical Isotopes Research Center, Peking University, China; 3Peking University, China
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Synthesis of photoactivatable HBED-CC and immunoPET of the hepatocyte growth factor receptor c-MET using photoradiolabelled [68Ga]GaHBED-CC-MetMAb R. Fay1, M. Gut2, J. Holland2 1University of Zurich, Switzerland; 2Department of Chemistry, University of Zürich, Switzerland
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Preclinical evaluation of a 68Ga-labeled bombesin antagonist comprising the bifunctional chelator NODIA-Me A. Schmidtke, M. Gut1, R. Fay2, J. Holland1, S. Ezziddin3, M. Bartholomae3 1Department of Chemistry, University of Zürich, Switzerland; 2University of Zürich, Switzerland; 3Medical Center, Saarland University, Germany In-vivo PET imaging of αvβ8-integrin J. Notni, A. Wurzer, F. Reichart, O. Maltsev, K. Steiger, R. Beck, H. Wester, M. Schwaiger, H. Kessler Technical University Munich, Germany Trans-cyclooctene-functionalized PeptoBrushes with improved reaction kinetics of the tetrazine ligation for pretargeted nuclear imaging J. Steen1, K. Nørregard2, K. Johann3, J. Jørgensen2, D. Svatunek4, A. Birke3, P. Edem7, R. Rossin6, C. Seidl3, F. Schmid5, M. Robillard6, H. Mikula4, J. Kristensen7, M. Barz3, A. Kjær2, M. Herth8 1Department of Drug Design and Pharmacology, University of Copenhagen, Denmark; 2Cluster for Molecular Imaging, Department of Biomedical Sciences, University of Copenhagen, Denmark; 3Institute of Organic Chemistry, Johannes Gutenberg University, Germany; 4Institute of Applied Synthetic Chemistry, Technische Universität Wien (TU Wien), Austria; 5Institute of Physics, Johannes Gutenberg University, Germany; 6Tagworks Pharmaceuticals, Netherlands; 7Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; 8Univesity of Copenhagen, Sweden Noninvasive imaging of CD38 using 64Cu-labeled F (ab)2 fragment from daratumumab in lymphoma models L. Kang1, D. Jiang2, W. Wei3, D. Ni2, J. Engle4, R. Wang1, W. Cai2 1Peking University First Hospital, China; 2University of Wisconsin-Madison, USA; 3Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, China; 4Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA PET imaging of gastrin-releasing peptide receptor with a novel 68Ga-labeled bombesin analogue J. Lau, E. Rousseau, Z. Zhang, C. Uribe, H. Kuo, J. Zeisler, C. Zhang, D. Kwon, K. Lin, F. Benard BC Cancer Research Centre, Canada Development of 18F-fluoroglycosylated PSMA ligands with improved kidney clearance behavior R. Potemkin, B. Strauch, M. Geisthoff, T. Kuwert, O. Prante, S. Maschauer Department of Nuclear Medicine, Molecular Imaging, and Radiochemistry, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany
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Radiofluorination of a COX-1 specific ligand based on two nucleophilic addition strategies C. Taddei, V. Pike National Institute of Mental Health, USA Kit-like 18F-labeling using triazole-linked conjugates for [18F]aluminum monofluoride complexation M. Walther1, C. Neuber1, R. Bergmann1, J. Pietzsch2, H. Pietzsch1 1Helmholtz-Zentrum Dresden-Rossendorf, Germany; 2Department Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Germany The efficient preparation of radiolabeled aromatic amino acids via Cu-mediated radiofluorination of Ni-complexes A. Craig1, N. Kolks2, E. Urusova3, J. Zischler1, B. Neumaier1, B. Zlatopolskiy4 1Forschungszentrum Jülich GmbH, Germany; 2Jülich Research Centre (FZJ), Germany; 3Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Forschungszentrum Jülich GmbH, Germany; 4Institute of Radiochemistry and Experimental Molecular Imaging (IREMB), University Hospital of Cologne, Germany Cyclic ketals as precursors for 3-deoxy-3-[18F]-fluororibose and its derivatives M. Parker1, M. Evans, D. Wilson University of California, San Francisco, USA Radiofluorination of non-activated aromatic prosthetic groups for efficient synthesis of fluorine-18 labelled ghrelin(1-8) analogues M. Lazarakos1, M. Kovacs2, L. Luyt1 1University of Western Ontario, Canada; 2The Lawson Health Research Institute, Canada Development of pyridine-based precursors for direct labeling of biomolecules M. Richard1, M. Roche2, S. Specklin1, B. Kuhnast1 1Imagerie Moléculaire In Vivo UMR1023 CEA, INSERM, CNRS, Université Paris Sud, Université Paris-Saclay, Service Hospitalier Frédéric Joliot, France; 2Imagerie Moléculaire In Vivo UMR1023 CEA, INSERM, CNRS, Université Paris-Sud, Université Paris-Saclay, Service Hospitalier Frédéric Joliot, Orsay, France
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Abstracts-Oral
DOI: 10.1002/jlcr.3724
SUPPLEMENT ARTICLE
23rd International Symposium on Radiopharmaceutical Sciences Key n ote lecture 1 O-01 | Pioneers require a spirit of determination and challenge: Milestones of PET radiopharmaceutical development Tatsuo Ido Neuroscience Research Institute, Gachon University, South Korea
On August 16, 1976, the first challengeable study of a human brain function was initiated at UPenn with the positron emitting radiopharmaceutical, 18F‐FDG. This was the first successful research of the regional glucose consumption mapping in human brain. And this was also a successful example of collaboration between different institutions and different research fields (Brookhaven/nuclear chemistry, NIMH/neurology, and UPenn/nuclear medicine). This is the one of great milestone of nuclear medicine development and led to PET functional image analysis (brain function and tumor function) with the well‐designed radiopharmaceuticals. In 1982, researchers at Johns Hopkins Medical School and Uppsala University collaborated in the undertaking of another challenge: neuro‐receptor imaging (dopamine D2) of the in‐vivo human brain using 11 C‐methylspiperone. This was a second milestone for development of molecular imaging. After this, the compounds related to signal transduction (agonist, antagonist) were labelled with 11C or 18F and applied to determine synapse activity. Dopaminergic, serotonergic, cholinergic, histaminergic, GABAergic, opioid, and glutamatergic receptors are able to determine by this method. Also, positron‐labelled MAO inhibitor and ACh‐esterase inhibitor are applied to diagnosis of PD and AD. A third milestone is the development of the theranostic application of radiopharmaceuticals to tumors. The 67Ga/68Ga labelled to a monoclonal antibody of tumor or shortened peptide linked DOTA was applied simultaneously to PET diagnosis and the internal radiation therapy of tumor. In this purpose, 89Zr is also selected because of its longer half‐life
(78.4 hr). Recently highlighted works in “Brain PET” research are the imaging of amyloidal plaque and active tau protein for AD patient. 11C‐ and 18F‐labelled thioflavin analogs have been developed as amyloidal plaque markers. Active tau protein image by 18F‐THK compound (quinoline derivative) is closer related to cell denature than the amyloidal plaque. Another prominent work is the imaging of inflammation that may be important to find tissue denature at early stage in PD, AD, and other neurodegenerative diseases. For this purpose, TSPO (translocator protein) ligand (phenoxyphenyl acetamide and oxopurine derivative) is labelled with 11C and 18F. These pioneering studies do not proceed without the spirit of determination and challenge. Do not hesitate to try your idea. Carefully planned research will lead to new developments and, perhaps, to unexpected but positive results. Never give up easily, And, finally, enjoy your research efforts and results!
Keynote l ecture 2 O-02 | Clinical translation of molecular imaging in nuclear medicine: PUMCH experience Fang Li1,2,3,4 1
Peking Union Medical College Hospital, China; 2 Beijing Key Laboratory
of Molecular Imaging Diagnosis and Treatment of Nuclear Medicine, China; 3 China Association of Nuclear Medicine Equipment, China; 4
Chinese Journal of Nuclear Medicine and Molecular Imaging, China
Translational medicine is a rapidly growing discipline in biomedical research that aims to expedite the discovery of new diagnostic tools and treatments by using a multi‐ disciplinary “bench‐to‐bedside” approach. Molecular imaging, originated from the need to better understand fundamental molecular pathways inside organisms in a noninvasive manner, has a deep impact in translational medicine, contributing to the developments of new drugs
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SUPPLEMENT ARTICLES
and theranostic approaches. Nuclear medicine, a highlighted molecular imaging modality in clinics, has a rapid development in recent decades due to discoveries and clinical translation of novel molecular probes targeting various diseases. It promotes mutual translation of basic research and clinical practice and makes medical achievements. Peking Union Medical College Hospital (PUMCH) has a heritage in translational medicine since 1920s. When PUMCH was established, it has always been advocated that the combination of basic research and clinical practice, the “bench‐to‐beside” approach, must be implemented in guidelines of scientific research. Dr. Liu Shihao, a pioneer in endocrinology in China, was devoted to the research in mechanism of insulin and insulinoma in 1930s and researched in bone metabolism and osteodystrophy in 1930s; Dr. Song Hongzhao has turned choriocarcinoma, a highly malignant tumor with over 90% mortality rate, to a curable disease based on his work since 1950s. In the new era of PUMCH, translational medicine research is still the key point in scientific research, and the National Center for Translational Medicine is being set up. In Nuclear Medicine Department of PUMCH, translational study of molecular imaging is crucial in scientific development in recent decades. One of the most successful works in translational study in nuclear medicine in PUMCH is the somatostatin receptor‐based theranostic approach in neuroendocrine tumors. We have started somatostatin receptor imaging studies since 1990s and then made many achievements to improve the molecular agent, clinical application, and radioligand theranostics, which has greatly changed the clinical practice of neuroendocrine tumors. Studies in insulinoma in PUMCH have always taken the leading place worldwide since the 1st case of insulinoma in China was successfully resected in PUMCH in 1930s. Advances in nuclear medicine in recent years have greatly improved the preoperative detection rate of insulinoma, making the “occult” tumor into a “easy‐to‐find” disease. With such efforts in translational studies of molecular imaging, many clinical dilemmas as diagnosis of neuroendocrine tumors, localizing tumor induced osteomalacia, occult insulinomas, biochemical recurrent prostate cancer, etc, have been solved with the clinical translation in novel molecular imaging. The research achievements were highly glorified in international scientific fields and clinical practice. There are two highlighted roadblocks in translational medicine: the first block prevents basic research findings from being tested in a clinical setting; the second prevents proven interventions from becoming standard practice. The first translational block has been greatly improved with implementation of “bench‐to‐bedside” approach. However, the second roadblock is one of the most
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important issues that still need to be improved, in order to make translational study to authentic clinical significant achievements.
Radiolabeled compounds ‐ oncology (i ma gi ng ) s es si o n 1 O-03 | Bispecific anti‐GRPR/PSMA heterodimer for PET and SPECT imaging diagnostic of prostate cancer Anna Orlova1; Bogdan Mitran1; Zohreh Varasteh1; Ayman Abouzayed1; Sara Rinne1; Mats Larhed2; Vladimir Tolmachev1; Ulrika Rosenström1 1
Uppsala University, Sweden; 2 Department of Medicinal Chemistry,
Science for Life Laboratory, Uppsala University, Sweden
Objectives Prostate cancer (PCa) belongs to the most heterogeneous malignant tumours, both histologically and clinically. Correct staging of PCa is crucial for patient management and is an urgent clinical need. Imaging of PCa using radiolabelled agents targeting cell‐surface proteins overexpressed in PCa is a valuable approach to improve diagnostic accuracy. Gastrin‐releasing peptide receptor (GRPR) and prostate‐specific membrane antigen (PSMA) are cell surface targets strongly associated with PCa. GRPRs are expressed at high density in prostatic intraepithelial neoplasias, primary and invasive PCa. Expression of GRPR in PCa tends to decrease with further disease progression. Expression of PSMA is low in normal prostate tissue, but is increased in PCa with progression and is significantly up‐regulated as tumours dedifferentiate into higher grade, androgen‐insensitive and metastatic lesions. No one single imaging tracer provides a satisfactory staging in PCa patients due to changes in PCa cells phenotype in disease progression. Bispecific anti‐GRPR/PSMA molecular imaging agent will improve staging of the disease due to specificity to receptors overexpressed both in earlier and later stage of the PCa. Methods Bispecific anti‐GRPR/PSMA dimer NOTA‐DUPA‐RM26 was designed by combining the peptidomimetic PSMA inhibitor Glu‐urea‐Glu and the GRPR binding peptide RM26 (D‐Phe‐Gln‐Trp‐Ala‐Val‐Gly‐His‐Sta‐Leu‐NH2) via (CH2)8‐Glu (NOTA)‐(PEG)6 and produced using a combination of solid‐phase and manual peptide synthesis. NOTA‐DUPA‐RM26 was labelled with indium‐111 and gallium‐68. In vitro characterisation of radiolabelled NOTA‐DUPA‐RM26 (binding specificity, cellular processing, and affinity determination) was performed using
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PC‐3, LNCaP, and PC‐3‐pip cell lines expressing GRPR, PSMA and both GRPR and PSMA, respectively. In vivo specificity and biodistribution of the agent was studied in mice bearing PC‐3‐pip xenografts. Visualisation of GRPR/PSMA‐expression was done using [68Ga]Ga‐ NOTA‐DUPA‐RM26 (PET) and [111In]In‐NOTA‐DUPA‐ RM26 (SPECT). Results NH2‐(CH2)8‐Glu (Aloc protected)‐(PEG)6‐RM26 was synthesized using standard Fmoc‐peptide chemistry and coupled with (S)‐5‐(tert‐butoxy)‐4‐(3‐((S)‐1,5‐di‐tert‐ butoxy‐1,5‐dioxopentan‐2‐yl)ureido)‐5‐oxopentanoic acid.
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NOTA chelator was coupled after Aloc deprotection. Cleavage of the product and deprotection were followed by HPLC purification. The peptide was isolated via RP‐HPLC and LC‐MS confirmed the identity of the compound. Product purity was over 95%. NOTA‐DUPA‐ RM26 was labelled with 111In with radiochemical yield of 99 ± 1% and with 68Ga with radiochemical yield of 98.8 ± 0.3% (determined by ITLC). Both labelled products demonstrated high stability of radiometal‐NOTA complex and specific binding to receptors in vitro and in vivo. In PC‐3‐pip xenografts expressing PSMA and GRPR, tumour uptake of both [68Ga]Ga‐NOTA‐DUPA‐RM26 (8 ± 2%ID/
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g) and [111In]In‐NOTA‐DUPA‐RM26 (12 ± 2%ID/g) exceeded uptake in any other studied tissues already at 1 h p.i. Blood clearance of radiotracers was rapid via renal excretion. Interestedly, [68Ga]Ga‐NOTA‐DUPA‐RM26 had significantly lower activity uptake in tumours but significantly higher uptake in liver than [111In]In‐NOTA‐ DUPA‐RM26. Activity uptake decreased with time in all studied tissues including tumours. Tumour‐to‐blood ratios 1 h pi were 24 ± 3 and 29 ± 4, tumour‐to‐intestine 11 ± 3 and 9 ± 3, tumour‐to‐muscle 80 ± 30 and 90 ± 30, and tumour‐to‐bone 30 ± 10 and 35 ± 15, for [68Ga]Ga‐ NOTA‐DUPA‐RM26 and [111In]In‐NOTA‐DUPA‐RM26, respectively. With time, tumour‐to‐organ ratios increased; however, improvement 3 h pi was more pronounced for [111In]In‐NOTA‐DUPA‐RM26, and 24 h pi improvement was observed only for tumour‐to‐blood ratio for this agent. MicroPET/CT and microSPECT/CT images confirm the ex vivo data (Figure). Tumour uptake dominated images for both radiotracers. Tumour uptake of [111In]In‐ NOTA‐DUPA‐RM26) was lower when conjugate was co‐ injected with PSMA‐ or GRPR‐targeting agents, and tumour uptake of both conjugates decreased when simultaneously co‐injected with PSMA‐ and GRPR‐targeting agents. Imaging contrast improved with time for [111In] In‐NOTA‐DUPA‐RM26); however, activity uptake in tumours decreased. Conclusions Bispecific anti‐GRPR/PSMA dimer NOTA‐DUPA‐RM26 for imaging of PCa labelled with galium‐68 (for PET) and indium‐111 (for SPECT) demonstrated its capacity to visualize GRPR and PSMA expression already 1 h pi and deserve further investigations. ACKNOWLEDGMENTS This work was supported by the Swedish Cancer Society (CAN2014‐474 and CAN 2017/425) and the Swedish Research Council (2015‐02509).
Radiolabeled compounds ‐ oncology ( i m a g i n g ) se s s i o n 1 O-04 | Pretargeted tumor imaging with 64Cu‐ labeled ultrastable cross‐bridged macrocyclic complex Abhinav Bhise1; Swarbhanu Sarkar2; Phuong Huynh2; Woonghee Lee2; Jung Young Kim3; Kyo Chul Lee4; Jeongsoo Yoo1 1
Kyungpook National University, Republic of Korea; 2 Department of
Molecular Medicine, Kyungpook National University, Republic of Korea; 3
KIRAMS(Korea Institue of Radiological and Medical Sciences), Republic
of Korea; 4 KIRAMS, Republic of Korea
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Objective Tumor pretargeting is a promising strategy for cancer diagnosis and therapy. It has been implemented successfully in different preclinical models with long circulating, highly specific monoclonal antibodies.1,2 The Diels‐ Alder reaction between tetrazine and strained alkene dienophile was found to be most promising click ligation variant for the biorthogonal reaction due to its high reaction rate, and absolute selectivity under in vivo condition. Cu‐64 has a mid‐long half‐life of 12.7 h, and researchers can allow the radiolabeled ligands to circulate enough long for better tumor‐to‐background ratio.3 In this case, the in vivo stability of radiolabeled ligand also plays key roles. Radiolabeled chelator must maintained its integrity under in vivo condition allowing no or minimal demetallation of free copper(II) ions from complexes. To address this issue, herein we demonstrate a new class of propylene cross‐bridged chelator, PCB‐TE2A‐tetrazine, which can maintain its in vivo stability until imaging time points and give excellent tumor‐to‐background ratio in antibody based pretargeted imaging. Methods The antibody was modified with transcyclooctene (TCO) and injected intravenously into Balb/c nude mice bearing MDB‐MB‐231 tumor xenograft. PCB‐TE2A‐ tetrazine was radiolabeled with 64Cu and injected to the same mice after 48 h injection of the antibody. The biodistribution was performed at 4 h and 8 h post‐ injection. Results The radiolabeling of PCB‐TE2A‐tetrazine with Cu‐64 was conducted at 80°C and isolated by HPLC in excellent radiochemical yield, >95%. Biodistribution at 4 h and 8 h postinjection showed tumor uptake of 25.37 and 25.15 %ID/g, respectively, with high tumor‐to‐organ ratios; tumor‐to‐muscle, tumor‐to‐blood, tumor‐to‐liver, and tumor‐to‐kidney ratio was 558, 128, 11, and 4, respectively, at 8 h post‐injection of the radiolabeled chelator. Conclusions The first demonstration of the 64Cu‐labeled cross‐bridged chelator in antibody pretargeting system was achieved successfully via inverse electron‐demand Diels‐Alder cycloaddition between tetrazine and transcyclooctene. Further animal PET imaging studies are going on and will be also presented. ACKNOWLEDGMENTS This work was supported by NRF (2016R1A2B4011546, 2013R1A4A1069507, 2017M2C2A1014006, 2017M2A2A 6A02018506, 2017R1D1A1B03033974, HI17C0221, and KRF 2016H1D3A1907667) and BK21 Plus KNU Biomedical Convergence Program, Korea.
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FIGURE 1
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Biodistribution data in MDA‐MB‐231 xenograft tumor model
R EF E RE N C E S 1. Patra M, Zarschler K, Pietzsch H‐J, Stephan H, Gasser G. Chem. Soc. Rev., 2016, 45, 6415‐6431. 2. Bailly C, Bodet‐Milin C, Rousseau C, Faivre‐Chauvet A, Kraeber‐ Bodéré F, Barbet J. EJNMMI Radiopharmacy and Chemistry, 2017, 2:6. 3. Zeglis BM, Sevak KK, Reiner T, Mohindra P, Carlin SD, Zanzonico P, Weissleder R, Lewis JS. J. Nucl. Med. 2013, 54, 1389–1396.
Radiolabeled compounds ‐ oncology ( i m a g i n g ) se s s i o n 1 O-05 | Targeting CD206+ tumor‐associated macrophages using a finely tuned albumin nano‐platform for earlier detection of breast cancer metastases Ji Yong Park1; Hyewon Chung2; Kyuwan Kim1; Minseok Suh1; Seung Hyeok Seok2; Yun‐Sang Lee3 1
Seoul National University, College of Medicine, Republic of Korea; 2 Seoul
National University, Republic of Korea; 3 Seoul National University Hospital, Republic of Korea
Introduction Currently, applied imaging modalities are limited by difficulties in detection of small metastatic lesions at an early‐ stage, thus missing the opportunity for an optimal response to therapeutic interventions. Given the earlier infiltration of CD206‐expressing tumor associated macrophages (CD206+ TAMs) than cancer cells in metastatic site, noninvasive imaging of CD206+ TAMs has a strong implication for earlier detection of metastasis in clinic. Here, we delineate the noninvasive detection of lung metastases using 111In and fluorescence labeled mannosylated human serum albumin (111In‐MSA‐FL), which binds to CD206, in orthotopic breast cancer xenograft models. The SPECT/CT images with 111In‐MSA‐FL demonstrates the strong correlation between quantitative uptake and metastatic burden and ultimately enables the identification of early‐stage metastatic lesions that are not discernible under standard imaging modalities including [18F]FDG‐PET/MRI.
Methods To synthesize a CD206‐targeted imaging probe that enabled the noninvasive imaging of CD206+ TAMs in vivo, the clickable albumin platform was prepared for conjugation of mannose, fluorescence dye and/or 111In. The number of azadibenzocyclooctyne (ADIBO) group for click reaction on the albumin platform was 8.4 ± 0.32, which was degree of functionalization (DOF) and calculated using UV‐Vis spectrophotometric method. Using this albumin platform, 5 molar excess of 1‐O‐(2‐(2‐ (2‐azidoethoxy)ethoxy)ethoxy)‐alpha‐D‐mannopyranoside (Man‐N3) was mixed with the ADIBO modified albumin platform. The number of mannosyl group on albumin platform was 4.1 ± 0.26, and then this mannosylated human serum albumin (MSA) was used for fluorescence (FNR648) labeling and/or 111In labeling to make MSA‐ FL or 111In‐MSA‐FL. The sizes of MSA derivatives were measured using dynamic light scattering (DLS) method and to be almost same with human serum albumin. Results First, 111In‐MSA‐FL was injected intravenously into this mice with orthotopic xenografts, and the SPECT/CT images were taken at 24 h post‐injection. In addition to substantial uptake in tumor, particularly tumor stroma at day 14, we demonstrated a clearly higher uptake in lung from 4T1‐bearing mice compared to tumor‐free mice at day 28. We next assessed the capability of the established 111 In‐MSA‐FL‐based CD206 imaging to discern metastatic lesion noninvasively at early stage. The 4T1‐bearing mice were imaged with both SPECT/CT using 111In‐MSA‐FL and PET/MRI using [18F]FDG from day 14 to 28 after cancer cell injection. Longitudinal monitoring showed the signal intensity at the future metastatic lung was gradually increased until day 28 when substantial metastatic nodules were observed, which was consistent with the flow cytometry analysis. Notably, we found 111In‐MSA‐FL signal in lung was higher compared to tumor‐free mice as early as day 14 and 21 post tumor inoculation as assessed by images‐based visual analysis (Figure 1a, b) and quantification of 111In‐MSA‐FL accumulation in dissected lung (Figure 1d) while there was no significant difference in [18F]FDG PET/MRI imaging between 4T1‐bearing mice and tumor‐free mice at this time (Fig. 1 a‐c). Thus, we
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demonstrated 111In‐MSA‐FL‐based imaging of CD206+ TAMs enabled the earlier detection of lung metastases than [18F]FDG PET/MRI. Conclusions Our results provide robust evidence that targeting CD206+ TAMs with 111In‐MSA‐FL could be a remarkable breakthrough to overcome the challenges in the early detection of metastasis and facilitates earlier therapeutic interventions. ACKNOWLEDGEMENTS This work was carried out by the research fund supported by the fund project of Park Yang Sook ‐ Chung Yung Ho in Seoul National University. Yun‐Sang Lee was supported by Radiation Technology R&D program (NRF‐ 2017M2A2A7A01021401) through the National Research Foundation of Korea (NRF).
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Radiolabeled compounds ‐ oncology (i ma gi ng ) s es si o n 1 O-06 | Improving pharmacokinetics of 99mTc‐ ref with PEG linkers for HER2‐targeted SPECT imaging of breast cancer Shuaifan Du1; Hannan Gao1; Chuangwei Luo1; Guangjie Yang1; Qi Luo2; Bing Jia1; Jiyun Shi3; Fan Wang1,2 1
Peking University, China; 2 Institute of Biophysics, CAS, China; 3 Institute
of Biophysics, CAS, China
Objectives Evaluating the expression status of human epidermal growth factor receptor‐2 (HER2) could predict the
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response of HER2‐targeted therapy in breast cancer. Previously, a HER2‐targeted H6F peptide (sequence: YLFFVFER) was developed as a SPECT imaging probe for HER2‐positive breast tumor. However, the 99mTc‐H6F probe was strictly limited for further clinical application because the poor water solubility and metabolic stability, as well as high gallbladder uptake. In this study, the Retro‐inverso ppD‐peptide (ref peptide full sequence: refvffly) of H6F was designed as a novel SPECT imaging probe, and PEGylation was further introduced into the probe to improve its metabolic stability and pharmacokinetics in vivo, so as to develop a promising noninvasive tool for discriminating HER2 status in breast cancer, and guiding the HER2‐targeted antibody treatment. The PEG4‐ref, PEG12‐ref, and PEG24‐ref peptides were designed and synthesized. Cell fluorescent staining and surface plasmon resonance (SPR) studies were firstly performed to validate the HER2‐binding affinity of ref peptides. Then, the PEG4‐ref/PEG12‐ref/PEG24‐ref peptides were radiolabeled with 99mTc for in vivo evaluation 99m Tc‐PEG4‐ref/99mTc‐PEG12‐ref/99mTc‐ (termed as PEG24‐ref). The biodistribution and SPECT imaging of 99m Tc‐PEG4/PEG12/PEG24‐ref were performed in HER2‐ positive SKBR3 human breast tumor bearing mice.
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Blocking group and HER2‐negative MCF7 human breast tumor group were set as controls. Results Cell staining and SPR results showed that ref peptides had high HER2‐binding affinity in vitro. NanoScan SPECT/CT imaging results showed that the HER2‐positive SKBR3 breast tumors could be clearly visualized with all three ref peptide based probes. Besides tumor, kidneys showed high accumulation followed by the liver. The biodistribution results were consistent with the imaging results. All three tracers gave enhanced tumor uptake, compared to the previous tracer 99mTc‐H6F (1.48 ± 0.18 %ID/g). Among them, the 99mTc‐PEG4‐ref showed the highest tumor uptake (3.76 ± 0.56 %ID/g) at 0.5 h p.i., but with highest kidney uptake (57.07 ± 6.55 %ID/g) and liver uptake (6.57 ± 0.94 %ID/ g) compared to that of further PEGylated 99mTc‐PEG12‐ ref (tumor: 3.29 ± 0.20 %ID/g, kidney: 35.52 ± 5.82 %ID/ g, liver: 2.57 ± 0.67 %ID/g) and 99mTc‐PEG24‐ref (tumor: 2.82 ± 0.43 %ID/g, kidney: 36.07 ± 2.10 %ID/g, liver: 2.33 ± 0.23 %ID/g), respectively. The T/NT ratios, especially Tumor/Blood, Tumor/Liver, Tumor/Muscle, and Tumor/Lung of 99mTc‐PEG24‐ref, were enhanced compared to that of 99mTc‐PEG4‐ref. In general, the further
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PEGylation of 99mTc‐PEG24‐ref resulted in improved in vivo pharmacokinetic properties but with decreased tumor uptake in comparison of 99mTc‐PEG4‐ref. The tumor uptake of 99mTc‐PEG24‐ref was notably decreased in blocking and HER2‐negative MCF7 tumor groups, indicating the HER2‐specific targeting capability. Conclusions 99m Tc‐PEG24‐ref is a promising molecular probe for HER2‐ positive breast cancer imaging, which showed enhanced tumor targeting capability and improved in vivo stability, compared to previous 99mTc‐H6F. The further PEGylation of 99mTc‐PEG24‐ref given its more improved in vivo biocompatibility, pharmacokinetic properties, resulted in better T/NT ratios, in comparison of 99mTc‐PEG4‐ref. This novel tracer possesses great potential for clinical application in screening HER2‐positive breast cancer patients and monitoring the efficacy of HER2 antibody treatment. The further investigation is still in progress. Figure 1: Representative nanoScan SPECT/CT images of (a) 99mTc‐ PEG4‐ref (b) 99mTc‐PEG12‐ref (c) 99mTc‐PEG24‐ref in SKBR3 (HER2+) tumor model, and (d) 99mTc‐PEG24‐ref in SKBR3 (HER2+) v.s. MCF7 (HER2−) and SKBR3 (Block) tumor models. (e) Chemical structures of 99mTc‐ HYNIC‐PEGn‐ref. (f) Biodistribution of 99mTc‐PEG4/12/24‐ ref in SKBR3 tumor model, compared to previous probe 99m Tc‐PEG4‐H6F. (g) T/NT ratios of 99mTc‐PEG24‐ref v.s. 99m Tc‐PEG4‐ref in SKBR3 tumor model.
Radiochemistry ‐
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O-07 | Generation of 18F‐metal fluorides from [18F]HF generated by acidic QMA elution and application towards 18F‐fluorination/ring‐ opening of complex epoxides Stefan Verhoog1; Allen Brooks2; Wade Winton2; Andrew Mossine2; Melanie Sanford2; Peter Scott3 1
Merck & Co Inc, USA; 2 University of Michigan, USA; 3 The University of
Michigan, USA
Objectives Anhydrous hydrogen fluoride (HF) is an effective fluorinating reagent with a unique reactivity profile due to its high acidity and its ability to form hydrogen bonded complexes with weak, non‐basic hydrogen bond acceptors. It is also an excellent reagent for the synthesis of well‐ defined metal fluoride salts, starting from a variety of different basic metal salt precursors.1 Previous work in our group has shown that [18F]HF can be easily generated through elution of [18F]F− trapped on a QMA, with the elution efficiency being related to the pKa of the acid
used.2 Our objective in this work was to use the [18F]HF thus produced in the synthesis of reactive 18F‐metal fluorides with a unique reactivity profile that is complementary to the reactivity of [18F]F− generated under more traditional, basic conditions in the presence of kryptand. As an example of such reactivity, we developed the fully automated 18F‐fluorination/ring opening of complex, sterically hindered epoxides using a [18F]FeF‐species generated from a combination of [18F]HF and Fe (acac)3. Methods Fluorine‐18 was produced by the 18O(p, n)18F nuclear reaction using a GE PETTrace cyclotron and delivered to a GE TRACERLab FXFN automated radiochemistry synthesis module followed by trapping on a Waters QMA SepPak Light Carb. This was followed by elution (as [18F]HF) with a solution of TFA in CH3CN/H2O 4:1 into a glassy carbon reactor, which had been charged with Fe (acac)3. The reaction was heated at 80°C for 10 min to trap [18F]HF and generate a [18F]FeF‐species, followed by azeotropic drying under vacuum/inert gas at 110°C. A solution of epoxide in dioxane was added, followed by heating at 120°C for 20 min under autogenous pressure. After cooling to 60°C, HPLC buffer was added and the mixture was purified by semi‐Prep HPLC to provide the 18F‐fluorohydrin product. Radiochemical identity and purity were confirmed using analytical HPLC, monitoring with UV and radiation detectors. Results Preliminary results show the synthesis and isolation of 4 complex 18F‐fluorohydrin products using a fully automated procedure in which acidic elution is utilized to generate [18F]HF, which is subsequently trapped as an [18F]FeF‐species. This species is then azeotropically dried to provide an effective reagent for 18F‐fluorination/ring‐opening of complex, sterically hindered epoxides (Figure 1). The reaction did not proceed when [18F] KF in combination with Kryptofix K222 was used as the 18 F‐fluorinating reagent. Conclusions A fully automated procedure was developed for the generation of [18F]HF through acidic elution, followed by trapping as a [18F]FeF‐species. This reagent was successfully used to open complex, sterically hindered epoxide substrates to provide the corresponding 18F‐fluorohydrins which were isolated after HPLC purification. The 18 F‐fluorohydrin products were synthesized in high radiochemical purity and in quantities sufficient for (pre‐)clinical imaging. The use of elution under acidic conditions to generate [18F]HF allows for synthesis of 18F‐metal fluorides with unique reactivity, which enable challenging 18 F‐fluorination reactions with complementary scope compared to basic [18F]F−/kryptand complexes.
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ACKNOWLEDGEMENTS This work was supported by NIH grant R01EB021155 from NIBIB. R EF E RE N C E S 1. Scholz, G.; Kemnitz, E. Modern Synthesis Processes and Reactivity of Fluorinated Compounds, 2017, 609‐649 2. Verhoog, S.; Brooks, A. F.; Mossine, A. V.; Scott, P. J. H. J. Nucl. Med. 2018, 59, Supplement 1:1064
Radiochemistry ‐
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O-08 | Pretargeted PET imaging using a dual click
18
F‐labeling strategy
Johanna Steen1; Christoph Denk2; Jesper Jørgensen3; Kamilla Nørregard3; Raffaella Rossin5; Martin Wilkovitsch2; Dennis Svatunek2; Patricia Edem6; Claudia Kuntner4; Thomas Wanek4; Marc Robillard5; Jesper Kristensen6; Andreas Kjær3; Hannes Mikula2; Matthias Herth7 1
Department of Drug Design and Pharmacology, University of
Copenhagen, Denmark; 2 Institute of Applied Synthetic Chemistry, Technische Universität Wien (TU Wien), Austria; 3 Cluster for Molecular Imaging, Department of Biomedical Sciences, University of Copenhagen, Denmark; 4 Health and Environment Department, Biomedical Systems, Austrian Institute of Technology (AIT), Austria; 5 Tagworks Pharmaceuticals, Netherlands; 6 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; 7 Univesity of Copenhagen, Sweden
Objectives Pretargeted immuno‐positron emission tomography (PET) imaging using the bioorthogonal ligation between a radiolabeled tetrazine and a monoclonal antibody (mAb) modified with trans‐cyclooctene (TCO) allows for the use of short‐lived radionuclides, such as fluorine‐18. However, direct 18F‐fluorination of
tetrazines has been reported to be tedious due to the sensitivity of the tetrazine scaffold.1,2 Thus, the objective of the present study was to explore a suitable indirect labeling approach, by which the combination of different building blocks would give us access to a library of 18F‐ labeled tetrazines with high structural diversity, including reactive structures that have previously proven difficult to access. The newly developed 18F‐labeled tetrazines were going to be used to image the tumor accumulation of the TAG72‐targeting mAb CC49 in human colon carcinoma.3 Methods The Cu‐catalyzed azide‐alkyne [3 + 2] cycloaddition (CuAAC) was identified as a strategy to access a tetrazine library. The library was made up from alkyne‐modified tetrazines in combination with 18F/19F‐fluorinated azides (Figure 1). The reference compounds were evaluated in an in‐house developed blocking assay to assess their potential as radioligands for pretargeting. The assay was performed in nude BALB/c mice bearing subcutaneous colon carcinoma LS174T xenografts. The mice were pretreated with TCO‐modified CC49 (CC49‐TCO, 100 μg, 6.7 nmol, ~7 TCO/mAb) 72 h prior to the experiments, in which the ability of the tetrazines to block a previously described 111In‐labeled tetrazine was studied.4 All 18F‐labeled tetrazines were evaluated in naïve mice for stability and biodistribution assessment. Subsequent pretargeted PET studies were performed using the same tumor model and mAb as for the blocking assay. PET/CT imaging was performed 1 h after tracer administration to determine tumor uptake. Results The 18F‐labeled tetrazines were successfully obtained via the CuAAC in decay corrected radiochemical yields up to 68% and high radiochemical purity (>94%). The blocking effects of their non‐radioactive analogs were correlated to parameters such as reaction kinetics and lipophilicity. In general, high rate constants >200 M−1 s−1 with a calculated distribution coefficient
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(clogD7.4) below 0.5 were favorable for a promising in vivo behavior. These results and biodistribution studies guided the selection of a group of 18F‐labeled tetrazines that was evaluated in pretargeted PET experiments. The results from the PET studies were in line with the predicted outcome from the assay. The tetrazine with the lowest clogD7.4 and a high rate constant (>200 M−1 s−1) was identified as a promising lead compound (Figure 1, tetrazine 3 combined with azide [18F]c) with a tumor uptake of 2.08 ± 0.24% ID/g. High radioactivity levels were observed in the blood pool (tumor‐to‐blood ratio was 0.75), arising from the ligation between 18F‐labeled tetrazine and the still circulating CC49‐TCO. Conclusion A small library of structurally diverse 18F‐labeled tetrazines was accessible via the CuAAC. Evaluation of the library revealed a tetrazine lead compound, which was able to bind to the mAb at the tumor‐site under high molar activity conditions. However, residual mAb in the blood remains a challenge. Current efforts are directed toward exploring clearing or masking agents, as well as developing a group of second‐generation tetrazines with higher hydrophilicity to potentially increase the tumor uptake further. ACKNOWLEDGMENTS The authors greatly acknowledge the H2020 project Click‐it, under grant agreement no. 668532, for financial support and the technical staff at the Department of
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Clinical Physiology, Nuclear Medicine and PET at Rigshospitalet, Denmark. RE FER EN CES 1. Denk C. et al., Angew. Chem. Int.Edit., 2014, 53, 9655–9659. 2. Li Z. et al., Chem Commun., 2010, 46, 8043–8045. 3. Rossin, R. et al., Bioconjug. Chem., 2013, 24, 1210‐1217. 4. Rossin R. et al., Angew. Chem. Int. Edit., 2010, 49, 3375–3378.
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O-09 | Development of high affinity 18F‐ labelled radiotracers for PET imaging of the adenosine A2A receptor Thu Hang Lai1; Susann Schroeder1; Friedrich‐Alexander Ludwig2; Steffen Fischer3; Rares Moldovan4; Matthias Scheunemann1; Sladjana Dukic‐Stefanovic1; Winnie Deuther‐Conrad1; Jorg Steinbach1; Peter Brust1 1
Helmholtz‐Zentrum Dresden‐Rossendorf, Germany; 2 Department of
Neuroradiopharmaceuticals, Institute for Radiopharmaceutical Cancer Research, Helmholtz‐Zentrum Dresden‐Rossendorf, Research Site Leipzig, Germany; 3 HZDR, FS Leipzig, Germany; 4 Institute of Radiopharmaceutical Cancer Research, Helmholtz‐Zentrum Dresden Rossendorf, Germany
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Objectives The adenosine A2A receptor (A2AR) is a G‐protein‐ coupled‐receptor which is mainly expressed in the basal ganglia (including striatum) of the brain and in cells of the immune system. Radiotracers for A2AR imaging have emerged as promising candidates for the diagnosis of neurodegenerative and neurooncological diseases. Aiming at the development of such radiotracer with improved molecular imaging properties, a library of 21 fluorinated pyrazolo[2,3‐d]pyrimidine derivatives was synthesized based on a recently published lead compound [1]. Among those, the high affinity 4‐fluorobenzyl derivate 1 (Ki (hA2A) = 5.3 nM; Ki (hA1) = 220 nM) and the 2‐fluorobenzyl derivate 2(Ki (hA2A) = 2.1 nM; Ki (hA1) = 147 nM) were chosen for 18F isotopic labelling although the introduction of 18F at non‐activated aromatic positions is challenging. Herein, we report on the radiosyntheses of [18F]1 and [18F]2 via an alcohol‐ enhanced copper‐mediated one‐step radiofluorination and their first biological evaluation. Methods Three different labelling strategies for the synthesis of [18F]1 have been investigated (Figure 1). The first two were using [18F]fluorobenzaldehyde ([18F]B) as intermediate, which was produced by nucleophilic radiofluorination of a trimethylammonium precursor of type A (step a). Compound [18F]B was used either in a reductive amination reaction (step b) or it was further reduced to the corresponding alcohol (step c) followed by an Appel bromination to get [18F]C (step d), which
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was finally used in a benzylation reaction (step e). The third strategy, a one‐step approach, started from the boronic acid pinacol ester precursor of type D employing [18F]TBAF and Cu (OTf)2(py)4 in n‐BuOH/ DMA (step f). The specific binding of [18F]1 and [18F]2 was evaluated in vitro by autoradiography of mice brain slices using 1, 2 and ZM241385 as different blocking agents. Results The two‐ and four‐step labelling strategies resulted in an overall radiochemical yield of only 1.4% and 10%, respectively, for [18F]1 (non‐isolated). Therefore, [18F]1 and [18F]2 were prepared by an alcohol‐enhanced copper‐ mediated one‐step radiolabelling approach starting from the corresponding boronic acid pinacol ester precursor D. Compound [18F]1 was obtained with a radiochemical yield of 52 + 7% (n = 5, EOB), a molar activity of 135 + 64 GBq/μmol (n = 4, EOS), and a radiochemical purity of >98%. Compound [18F]2 was synthesized with a radiochemical yield of 9 + 1% (n = 2, EOB), a molar activity of 132 GBq/μmol (n = 1, EOS), and a radiochemical purity of >98%. In vitro autoradiography performed with [18F]2 showed high binding in the striatum, which could be blocked by selective A2AR ligands thus proving the specificity of the new radiotracer (Figure 1). Conclusions An efficient copper‐mediated one‐step radiolabelling procedure was established for two new high affinity A2AR radiotracers. In a first in vitro study on mice brain slices,