Theranostic mercury: 197(m)Hg with high specific activity for imaging and therapy DISSERTATION zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr. rer. nat.) vorgelegt der Fakultät Mathematik und Naturwissenschaften der Technischen Universität Dresden von Master of Science Chao Wang Born on 07. September 1988 in Harbin, PR China Submitted on: 14.09.2018 Date of defense:13.11.2018 Die Dissertation wurde in der Zeit von September 2014 bis September 2018 am Helmholtz-Zentrum Dresden-Rossendorf im Institut für Radiopharmazeutische Krebsforschung angefertigt. Reviewers: Prof. Dr. Jörg Steinbach (TU Dresden, HZDR) Prof. Dr. Gerd Wunderlich (TU Dresden) Table of Contents 1 Introduction and aim of the work .................................................................... 1 1.1 Introduction ........................................................................................................... 1 1.2 Aims of the Thesis ................................................................................................ 6 1.2.1 Major tasks of this work .................................................................................... 6 2 Theoretical background and literature survey .............................................. 9 2.1 Theranostics .......................................................................................................... 9 2.1.1 General ............................................................................................................. 9 2.1.2 Modalities for diagnostic: PET and SPECT ................................................... 10 2.1.3 Radionuclide therapy...................................................................................... 11 2.1.4 Radionuclide production for theranostics....................................................... 12 2.1.5 Metallic radionuclides for theranostics ........................................................... 13 2.2 The capability of 197(m)Hg for theranostics ........................................................ 15 2.2.1 Properties of the element Hg ......................................................................... 16 2.2.2 Isotopes of mercury ........................................................................................ 16 2.2.3 Production of the radiomercury isotopes (203Hg and 197(m)Hg) for potential medical uses ............................................................................................................ 18 2.2.4 Major decay processes of 197(m)Hg: promising for theranostics ..................... 20 2.2.5 Chemical properties of Hg and applications .................................................. 22 2.2.6 Hg chemistry: organometallic compounds ..................................................... 23 2.2.7 Hg-organometallics: the electrophilic aromatic substitution with trialkyltin- precursors ................................................................................................................ 25 2.2.8 Chemical behavior of mercury: Hg(II)-ion selective chemosensors .............. 27 2.2.9 The toxicology of mercury .............................................................................. 28 2.3 Medical studies with radio-mercury (203Hg and 197Hg) labeled radiopharmaceuticals in the past............................................................................ 31 2.3.1 203Hg labeled chlormerodrin (Neohydrin) ....................................................... 31 197 197 2.3.2 Hg labeled Chlormerodrin (Neohydrin) and unlabeled [ Hg]HgCl2 ......... 31 2.3.3 197(m)Hg labeled bio-molecules based on Hg-S bond in the past ................... 33 2.4 Conclusion for the own investigation .............................................................. 35 3 Results and discussions ................................................................................ 38 3.1 Radionuclide production of 197(m)Hg .................................................................. 38 3.1.1 197Au(p,n)197(m)Hg reaction .............................................................................. 38 3.1.2 197Au(d,2n)197(m)Hg reaction ............................................................................ 39 3.2 Radiochemical separation methods of 197(m)Hg from the gold target ........... 41 3.2.1 Commercial mercury chelating resin for 197(m)Hg separation ......................... 41 3.2.2 Separation by evaporation/distillation ............................................................ 42 3.2.3 Liquid-liquid extraction with methyl-isobutyl-ketone (MIBK) .......................... 44 3.2.4 Liquid-solid extraction with TEVA resin .......................................................... 45 3.2.5 Liquid-solid extraction with LN resin .............................................................. 46 3.2.6 Summary ........................................................................................................ 49 3.3 Development and evaluation of 197(m)Hg labeling units .................................. 54 3.3.1 General remarks to n.c.a.197(m)Hg labeling ..................................................... 54 3.3.2 Hg-N compounds: Radiolabeling and stability studies of N-bearing macrocyclic ligands with 197(m)Hg ............................................................................. 56 3.3.3 Hg-S compounds: Radiolabeling and characterization of mercury tetra- thiolate compounds ([197(m)Hg]2) .............................................................................. 60 3.3.4 Hg-S compounds: Synthesis, radiolabeling and stability studies of the bipodal dithiocarbamate ([197(m)Hg]4) ................................................................................... 63 197(m) 197(m) 3.3.5 Hg-S or Hg-Te bonds: Hg labeled NS2 chelating motif ([ Hg]6) and 197(m) NTe2 chelating motif ([ Hg]8) ............................................................................. 65 3.3.6 Hg-organometallics: Radiosynthesis of [197(m)Hg]phenyl-HgCl and ([197(m)Hg]10) and [197(m)Hg]diphenyl-Hg ([197(m)Hg]11) via electrophilic aromatic substitution of tributyl(phenyl)stannane precursor .................................................. 69 3.3.7 Hg-organometallics: Radiosynthesis of [197(m)Hg]13 and [197(m)Hg]14 via electrophilic aromatic substitution with imidazole derivative (12) precursor .......... 73 3.3.8 Hg-organometallics: alternative approaches for the radiosynthesis of arylmercury with tetraorganoborate precursors ...................................................... 81 3.3.9 Hg-organometallics: 197(m)Hg labeled N-heterocyclic carbene complexes ([197(m)Hg]19) ............................................................................................................ 83 3.3.10 Summary ...................................................................................................... 87 3.4 Asymmetric 197(m)Hg labeling units: radiosynthesis of dithiocarbamate arylmercury compounds .......................................................................................... 89 3.4.1 Synthesis of dithiocarbamates ....................................................................... 89 3.4.2 Radiosynthesis of symmetric 197(m)Hg labeled dithiocarbamates ([197(m)Hg]26) ................................................................................................................................. 90 3.4.3 The Radiosynthesis strategy of asymmetric dithiocarbamate arylmercury compounds .............................................................................................................. 92 3.4.4 Radiosynthesis, stability and non-radioactive corresponding studies of asymmetric [197(m)Hg]12-Hg-25 ([197(m)Hg]27) .......................................................... 94 3.4.5 Radiosynthesis of asymmetric compounds [197(m)Hg]28 and [197(m)Hg]29 .... 100 3.4.6 SPECT imaging of [197(m)Hg]28 and [197(m)Hg]29 in healthy rats .................. 101 3.4.7 Radiosynthesis of other asymmetric dithiocarbamate arylmercury compounds ............................................................................................................ 102 3.4.8 Summary ...................................................................................................... 103 3.5 197(m)Hg labeling of specific targeting molecules........................................... 104 3.5.1 Radiosynthesis of 197(m)Hg labeled agmatine compounds ([197(m)Hg]35 and [197(m)Hg]36). ........................................................................................................... 105 3.5.2 Radiosynthesis of asymmetric 197(m)Hg labeled PSMA compound ([197(m)Hg]39). .......................................................................................................... 111 3.5.3 Radiosynthesis of [197(m)Hg]41 for the detection of reactive oxygen species ............................................................................................................................... 114 3.5.4 Summary ...................................................................................................... 116 4 Conclusions ................................................................................................... 118 4.1 Radiomercury production in sufficient quantity and quality....................... 118 4.2 Development of a reliable method for Hg/Au separation ............................. 118 4.3 Development of application available 197(m)Hg labeling units ...................... 119 4.4 Outlook to 197(m)Hg labeled small targeting molecules. ................................. 123 5 Experimental part .........................................................................................