Functionalized Bis(thiosemicarbazonato) Complexes of Zinc and Copper: Synthetic Platforms Toward Site-Specific Radiopharmaceuticals Jason P. Holland, ² Franklin I. Aigbirhio, ‡ Helen M. Betts, ² Paul D. Bonnitcha, ² Paul Burke, ‡ Martin Christlieb, ² Grant C. Churchill, § Andrew R. Cowley, ² Jonathan R. Dilworth,* ,² Paul S. Donnelly, | Jennifer C. Green, ² Josephine M. Peach, ² Sridhar R. Vasudevan, § and John E. Warren ⊥ Chemistry Research Laboratory, Department of Chemistry, UniVersity of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, UniVersity of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom, Department of Pharmacology, UniVersity of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom, School of Chemistry, UniVersity of Melbourne, ParkVille, Victoria 3010, Australia, and CCLRC Daresbury Laboratory, Daresbury, Warrington WA4 4AD, United Kingdom Received August 17, 2006 Two new types of unsymmetrical bis(thiosemicarbazone) proligands and their neutral zinc(II) and copper(II) complexes have been synthesized. These bifunctional ligands both chelate the metal ions and provide pendent amino groups that can be readily functionalized with biologically active molecules. Functionalization has been demonstrated by the synthesis of three water-soluble glucose conjugates of the new zinc(II) bis(thiosemicarbazonato) complexes, and their copper(II) analogues have been prepared in aqueous solution via transmetalation. A range of techniques including NMR, electron paramagnetic resonance, cyclic voltammetry, high-performance liquid chromatography (HPLC), UV/vis, and fluorescence emission spectroscopy have been used to characterize the complexes. Four compounds, including two zinc(II) complexes, have been characterized by X-ray crystallography. The connectivity and conformation of the glucose conjugates have been assigned by NMR spectroscopy. Time-dependent density functional theory calculations have been used to assign the electronic transitions of the copper(II) bis(thiosemicarbazonato) chromophore. Two copper-64-radiolabeled complexes, including one glucose conjugate, have been prepared and characterized using radio-HPLC, and transmetalation is shown to be a viable method for radiolabeling compounds with copper radionuclides. Preliminary cell washout studies have been performed under normoxic conditions, and the uptake and intracellular distribution have been studied using confocal fluorescence microscopy. Introduction Over recent years, advances in imaging technology and the potential of nuclear medicine to provide site-specific therapy have generated intense interest in the design of new imaging agents. 1-4 Since Brownell and Sweet 5,6 recorded the first medical images of localized brain tumors using positrons in 1953 and the development of the metabolic imaging agent [ 18 F]-2-fluoro-2-deoxy-D-glucose ( 18 FDG), during the 1970s, the use of positron emission tomography (PET) as a diagnostic tool has expanded rapidly. 7-10 Although other imaging techniques such as computerized tomography (CT) * To whom correspondence should be addressed. E-mail: jon.dilworth@ chem.ox.ac.uk. Tel: +44 (0)1865 285151. ² Department of Chemistry, University of Oxford. ‡ University of Cambridge. § Department of Pharmacology, University of Oxford. | University of Melbourne. ⊥ CCLRC Daresbury Laboratory. (1) Smith, S. V. J. Inorg. Biochem. 2004, 98 (11), 1874. (2) Blower, P. J.; Lewis, J. S.; Zweit, J. Nucl. Med. Biol. 1996, 23 (8), 957. (3) Anderson, C. J.; Welch, M. J. Chem. ReV. 1999, 99 (9), 2219. (4) Volkert, W. A.; Hoffman, T. J. Chem. ReV. 1999, 99 (9), 2269. (5) Brownell, G. L.; Sweet, W. H. Nucleonics 1953, 11, 40. (6) Sweet, W. H. N. Eng. J. Med. 1951, 245, 875. (7) Wrenn, F. R., Jr.; Good, M. L.; Handler, P. Science 1951, 113 (2940), 525. (8) Adam, M. J.; Wilbur, D. S. Chem. Soc. ReV. 2005, 34 (2), 153. (9) Gallagher, B. M.; Ansari, A.; Atkins, H.; Casella, V.; Christman, D. R.; Fowler, J. S.; Ido, T.; MacGregor, R. R.; Som, P.; Wan, C. N.; Wolf, A. P.; Kuhl, D. E.; Reivich, M. J. Nucl. Med. 1977, 18 (10), 990. (10) Gallagher, B. M.; Fowler, J. S.; Gutterson, N. I.; MacGregor, R. R.; Wan, C. N.; Wolf, A. P. J. Nucl. Med. 1978, 19 (10), 1154. Inorg. Chem. 2007, 46, 465-485 10.1021/ic0615628 CCC: $37.00 © 2007 American Chemical Society Inorganic Chemistry, Vol. 46, No. 2, 2007 465 Published on Web 12/22/2006