molecules Current Aspects of Radiopharma- ceutical Chemistry Edited by Peter Brust Printed Edition of the Special Issue Published in Molecules www.mdpi.com/journal/molecules Current Aspects of Radiopharmaceutical Chemistry Current Aspects of Radiopharmaceutical Chemistry Special Issue Editor Peter Brust MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editor Peter Brust Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig Germany Editorial Office MDPI St. Alban-Anlage 66 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Molecules (ISSN 1420-3049) from 2017 to 2018 (available at: http://www.mdpi.com/journal/molecules/ special issues/Radiopharmaceutical Chemistry) For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03897-162-7 (Pbk) ISBN 978-3-03897-163-4 (PDF) Cover image courtesy of Helmholtz-Zentrum Dresden-Rossendorf. Articles in this volume are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book taken as a whole is c 2018 MDPI, Basel, Switzerland, distributed under the terms and conditions of the Creative Commons license CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents About the Special Issue Editor ...................................... vii Preface to ”Current Aspects of Radiopharmaceutical Chemistry” ................. ix Nikunj B. Bhatt, Darpan N. Pandya and Thaddeus J. Wadas Recent Advances in Zirconium-89 Chelator Development Reprinted from: Molecules 2018, 23, 638, doi: 10.3390/molecules23030638 .............. 1 J´an Kozempel, Olga Mokhodoeva and Martin Vlk Progress in Targeted Alpha-Particle Therapy. What We Learned about Recoils Release from In Vivo Generators Reprinted from: Molecules 2018, 23, 581, doi: 10.3390/molecules23030581 .............. 25 Licia Uccelli, Alessandra Boschi, Petra Martini, Corrado Cittanti, Stefania Bertelli, Doretta Bortolotti, Elena Govoni, Luca Lodi, Simona Romani, Samanta Zaccaria, Elisa Zappaterra, Donatella Farina, Carlotta Rizzo, Melchiore Giganti and Mirco Bartolomei Influence of Storage Temperature on Radiochemical Purity of 99mTc-Radiopharmaceuticals Reprinted from: Molecules 2018, 23, 661, doi: 10.3390/molecules23030661 .............. 43 Sara Roslin, Peter Brandt, Patrik Nordeman, Mats Larhed, Luke R. Odell and Jonas Eriksson Synthesis of 11C-Labelled Ureas by Palladium(II)-Mediated Oxidative Carbonylation Reprinted from: Molecules 2017, 22, 1688, doi: 10.3390/molecules22101688 ............. 51 Tetsuro Tago and Jun Toyohara Advances in the Development of PET Ligands Targeting Histone Deacetylases for the Assessment of Neurodegenerative Diseases Reprinted from: Molecules 2018, 23, 300, doi: 10.3390/molecules23020300 .............. 72 Susann Schr¨oder, Barbara Wenzel, Winnie Deuther-Conrad, Rodrigo Teodoro, Mathias Kranz, Matthias Scheunemann, Ute Egerland, Norbert H¨ofgen, Detlef Briel, J¨org Steinbach and Peter Brust Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A Reprinted from: Molecules 2018, 23, 556, doi: 10.3390/molecules23030556 .............. 99 Nicolas Vignal, Salvatore Cisternino, Nathalie Rizzo-Padoin, Carine San, Fortune Hontonnou, Thibaut Gel´e, Xavier Decl`eves, Laure Sarda-Mantel and Benoˆıt Hosten [18F]FEPPA a TSPO Radioligand: Optimized Radiosynthesis and Evaluation as a PET Radiotracer for Brain Inflammation in a Peripheral LPS-Injected Mouse Model Reprinted from: Molecules 2018, 23, 1375, doi: 10.3390/molecules23061375 .............114 Bieneke Janssen, Danielle J. Vugts, Albert D. Windhorst and Robert H. Mach PET Imaging of Microglial Activation—Beyond Targeting TSPO Reprinted from: Molecules 2018, 23, 607, doi: 10.3390/molecules23030607 ..............130 Friedrich-Alexander Ludwig, Steffen Fischer, Ren´e Smits, Winnie Deuther-Conrad, Alexander Hoepping, Solveig Tiepolt, Marianne Patt, Osama Sabri and Peter Brust Exploring the Metabolism of (+)-[18F]Flubatine In Vitro and In Vivo: LC-MS/MS Aided † Identification of Radiometabolites in a Clinical PET Study Reprinted from: Molecules 2018, 23, 464, doi: 10.3390/molecules23020464 ..............144 v Teresa Mann, Jens Kurth, Alexander Hawlitschka, Jan Stenzel, Tobias Lindner, Stefan Polei, Alexander Hohn, Bernd J. Krause and Andreas Wree 18 [ F]Fallypride-PET/CT Analysis of the Dopamine D2/D3 Receptor in the Hemiparkinsonian Rat Brain Following Intrastriatal Botulinum Neurotoxin A Injection Reprinted from: Molecules 2018, 23, 587, doi: 10.3390/molecules23030587 ..............159 Mathias Kranz, Ralf Bergmann, Torsten Kniess, Birgit Belter, Christin Neuber, Zhengxin Cai, Gang Deng, Steffen Fischer, Jiangbing Zhou, Yiyun Huang, Peter Brust, Winnie Deuther-Conrad and Jens Pietzsch Bridging from Brain to Tumor Imaging: (S)-(−)- and (R)-(+)-[18F]Fluspidine for Investigation of † Sigma-1 Receptors in Tumor-Bearing Mice Reprinted from: Molecules 2018, 23, 702, doi: 10.3390/molecules23030702 ..............177 Cristina M ¨uller, Patrycja Guzik, Klaudia Siwowska, Susan Cohrs, Raffaella M. Schmid and Roger Schibli Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates Reprinted from: Molecules 2018, 23, 1465, doi: 10.3390/molecules23061465 .............190 vi About the Special Issue Editor Peter Brust, Prof., Dr., is a biologist. He received his M.S. in Immunology in 1981 and his Ph.D. in Neuroscience from Leipzig University in 1986. He worked as a postdoctoral fellow at Montreal Neurological Institute and Johns Hopkins University, Baltimore, from 1990 to 1991. He joined the Research Center Rossendorf (now known as Helmholtz-Zentrum Dresden-Rossendorf, HZDR) in 1992 and headed the Department of Biochemistry. Since 2002, he has been working in Leipzig, first at the Institute of Interdisciplinary Isotope Research and, after an operational transfer in 2010, again at the HZDR, where he leads the Department of Neuroradiopharmaceuticals. His main research interest is in radiotracer development for brain imaging with positron emission tomography, including brain tumor imaging (glioblastoma, brain metastases), imaging of blood-brain barrier transport of radiopharmaceuticals, and neuroimaging of the cholinergic system, second-messenger systems, and neuromodulatory processes. He has about 250 peer-reviewed publications and owns numerous patents. vii Preface to ”Current Aspects of Radiopharmaceutical Chemistry” Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are in vivo molecular imaging techniques which are widely used in nuclear medicine for the diagnosis and treatment follow-up of many major diseases. They use target-specific molecules as probes, which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiopharmaceuticals. Their design and development require a rather interdisciplinary process involving many different disciplines of natural sciences and medicine. In addition to their diagnostic and therapeutic applications in the field of nuclear medicine, radiopharmaceuticals are powerful tools for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, investigate the pathophysiology of diseases, discover potential drug candidates, and evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo. Furthermore, they allow molecular imaging studies in various small-animal models of disease, including genetically engineered animals. The current collection of articles provides unique examples covering all major aspects in the field. The first half, radiopharmacy, is more chemistry- related, while the second half, radiopharmacology, deals with the preclinical development of radiopharmaceuticals. The largest proportion of positron-emitting radionuclides is commonly produced in particle 68 68 accelerators, usually cyclotrons. More recently, generator systems, e.g., the Ge/ Ga generator, have shown great potential as a source of positron-emitting radionuclides for PET. Gallium-68, which has a relatively short half-life (68 min), is particularly suitable for the labeling of peptides that show rapid target tissue accumulation and clearance. PET investigation of monoclonal antibodies, which represent one of the fastest growing therapeutic groups, requires radionuclides with much longer half-lives. The decay half-life of zirconium-89 (3.3 d) matches the circulation half-lives of antibodies (usually in the order of days); therefore, it emerged as a suitable PET radionuclide for labeling. The review of Bhatt et al. focuses on recent advances in zirconium-89 chelation chemistry. Another major use of radiometals is in radionuclide therapy of cancer. Radium-223, an alpha- emitting radionuclide, has been approved for the treatment of bone metastasis in metastatic castration-resistant prostate cancer. In vivo generators are thought to combine the long half-life of a parent radionuclide with the high decay energy of the daughter to achieve high-dose targeted radiotherapy. On the other hand, they