DOI: 10.1002/cplu.201402031 Synthesis and Characterization of a Stable Copper(I) Complex for Radiopharmaceutical Applications Ewen Bodio, [a, b] Mohammed Boujtita, [a] Karine Julienne, [a] Patricia Le Saec, [c] SØbastien G. Gouin, [a] Jonathan Hamon, [d] Eric Renault, [a] and David Deniaud* [a] Introduction Over recent years, medical imaging has become one of the main interests in therapeutic chemistry. Progress in instrumen- tation and the need to diagnose diseases at their early stages are some of the reasons for such an interest. Moreover, identi- fying the target(s) of a drug and understanding the mecha- nism of action of a new compound are becoming essential re- quirements for their acceptance in clinical-phase trials. This has led to the development of the new field of theranostics. The term theranostics has been coined to describe this emerging area of research, which focuses on agents that could be used in both imaging and therapy. [1] In our case, this consists of taking advantage of the duality of an element such as copper, which possesses both a b + emitter ( 64 Cu), used as a positron emission tomography (PET) imaging agent, and a b  emitter ( 67 Cu), used as a radiotherapeutic entity. The long half-life of 64 Cu (t1 = 2 = 12.7 h) allows a satisfactory accumulation of radionuclides in the tumor. [2] Furthermore, 64 Cu presents a good spatial resolution for PET imaging, equiv- alent to 18 F. [3] Some studies have shown that it gives the high- est effective dose and, above all, that it can be used in prelimi- nary dosimetry studies for radioimmunotherapy (use of radiola- beled antibodies to target tumor cells and destroy them). [4] In fact, the key problem in radioimmunotherapy is to be able to measure the amount of radioactivity bound to the tumor cells (as this depends on the kind of cancer, the vector, and even on the patient). Thus, with 64 Cu, a PET image can be obtained and the radioactivity can be quantified. As the same vector can be used to transport 67 Cu to tumor cells, the pharmacoki- netics will be the same and the quantity of 67 Cu linked to the tumor will be known. To target copper selectively to cancerous tissues, a peptide, peptidomimetic, or an antibody can be used. The key element of this strategy is the bifunctional chelate (BFC), the entity that binds the radionuclide to the vector. An ideal BFC binds the targeted radiometal rapidly with a high specificity and yield. Furthermore, the resulting complex should be both thermody- namically stable and, more importantly, kinetically inert toward in vivo transchelation or transmetalation processes. To form a complex with copper, a large variety of acyclic, macrocyclic, and macrobicyclic polyamine BFCs have been studied and re- ported. [5] However, the choice of the chelator is critical given that recent studies have shown that it can influence the radio- labeling of the bioconjugate, its targeting, and its pharmacoki- netics. [6] Clearly, it is still important to develop new copper che- lators. Cyclen and cyclam macrocyclic derivatives have com- A highly stable copper(I) complex was obtained starting from a copper(II) salt. This compound was characterized by a combi- nation of several analytical techniques (UV/Vis spectroscopy, energy-dispersive X-ray spectroscopy, electrochemistry, and X-ray photoelectron spectroscopy) and was shown to present an N 4 Cu structure. These results were confirmed by a density functional calculations study of the binding energy and the electronic structure of model ligand and copper complexes. Preliminary tests of complexation showed a high ability of the corresponding ligand to chelate 64 Cu in very diluted medium, which is of interest for developing new positron emission to- mography imaging agents. The stability and the kinetic inert- ness of the complex are promising. In particular, it displayed good redox stability, which is important because in vivo reduc- tion or oxidation of the copper of Cu complexes can lead to demetalation. The rapid microwave-assisted strategy used to synthesize the ligand was applied to the synthesis of more than ten ligands. One of these was functionalized by an amino group to form a bifunctional chelate for a future bioconju- gation for applications in nuclear medicine. [a] Dr. E. Bodio, Dr. M. Boujtita, Dr. K. Julienne, Dr. S. G. Gouin, Dr. E. Renault, Dr. D. Deniaud LUNAM UniversitØ, CEISAM Chimie et InterdisciplinaritØ, Synthse, Analyse, ModØlisation UMR CNRS 6230, UFR des Sciences et des Techniques 2 rue de la Houssinire, BP 92208, 44322 Nantes Cedex 3 (France) E-mail : david.deniaud@univ-nantes.fr [b] Dr. E. Bodio Institut de Chimie MolØculaire de l’UniversitØ de Bourgogne UMR CNRS 6302, UniversitØ de Bourgogne 9 avenue A. Savary, BP 47870, 21078 Dijon (France) [c] P. Le Saec Centre de Recherche en CancØrologie de Nantes-Angers, UMR CNRS 6299 INSERM U892, Institut de Recherche ThØrapeutique, UniversitØ de Nantes 9 quai Moncousu, 44093 Nantes Cedex 1 (France) [d] J. Hamon IMN, Institut des MatØriaux Jean Rouxel, UMR CNRS 6502 UFR des Sciences et des Techniques 2 rue de la Houssinire, BP 92208, 44322 Nantes Cedex 3 (France) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cplu.201402031.  2014 Wiley-VCH Verlag GmbH & Co. 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