The five-step synthesis of a polydentate building block combining a cyclen-based macrocycle (DO3A) with N-(2-aminoethyl)propane-1,3-diamine, which are linked through the xylylen moiety as a rigid C-spacer is described. These two molecular parts were coupled by subsequent bromine atom substitution in 1,4-bis(bromomethyl)benzene. First, N-(2-aminoethyl)propane-1,3-diamine was protected by phthaloyl moieties and then it was reacted with 1,4-bis(bromomethyl)benzene to form (2-phthalimidoethyl)(3-phthalimido-prop-1-yl)(4-bromomethylbenzyl)amine (2). This compound underwent a substitution reaction with DO3A in the form of its tert-butyl esters leading to the intermediate 1-{4-[(2-phthalimidoethyl)(3-phthalimidoprop-1-yl)aminomethyl]phenylmethyl}-4,7,10-tris(t-butoxy-carbonylmethyl)-1,4,7,10-tetraazacyclododecane (3). The phthaloyl as well as the t-butyl protecting groups were removed in the next two reaction steps to form the final product 1-{4-[(2-aminoethyl)(3-aminoprop-1-yl)aminomethyl]phenylmethyl}-4,7,10-tris(carboxy-methyl)-1,4,7,10-tetraazacyclododecane (5). The intermediates 1-4 as well as the final product 5 were characterized by elemental analysis, mass spectrometry, and multinuclear (1H and 13C) and two-dimensional NMR spectroscopy. The final product 5 could serve as a potential building block in subsequent syntheses of binuclear complexes of lanthanides and/or transition metals.

Department of Inorganic Chemistry and Regional Centre of Advanced Technologies and Materials Faculty of Science Palacký University 17 listopadu 12 Olomouc CZ 77146 Czech Republic

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Merbach A., Helm L., Tóth É., editors. The Chemistry of Contrast Agents in Medicinal Magnetic Resonance Imaging. John Wiley & Sons; Chichester, UK: 2013.

Montgomery G.P., Murray B.S., New E.J., Pal R., Parker D. Cell-penetrating metal complex optical probes: Targeted and responsive systems based on lanthanide luminescence. Acc. Chem. Res. 2009;42:925–937. doi: 10.1021/ar800174z. PubMed DOI

Krause W., editor. Contrast Agents III, Radiopharmaceuticals—From Diagnosticts to Therapeutics. Springer; Heidelberg, Germany: 2005.

Tweedle M.F. Peptide-targeted diagnostics and radiotherapeutics. Acc. Chem. Res. 2009;42:958–968. doi: 10.1021/ar800215p. PubMed DOI

Atmani C., El Hajj F., Benmansour S., Marchivie M., Triki S., Conan F., Patinec V., Handel H., Dupouy G., Gómez-García C.J. Guidelines to design new spin crossover materials. Coord. Chem. Rev. 2010;254:1559–1569. doi: 10.1016/j.ccr.2009.11.004. DOI

Develay S., Tripier R., Bernier N., Le Baccon M., Patinec V., Serratrice G., Handel H. Cyclen based bis-macrocyclic ligands as phosphates receptors. A potentiometric and NMR study. Dalton Trans. 2005 doi: 10.1039/B507819A. PubMed DOI

König B., Svoboda J. Azamacrocyclic systems with different supramolecular function. In: Gloe K., editor. Macrocyclic Chemistry: Current Trends and Future Perspectives. Springer; Dordrecht, The Netherlands: 2005. pp. 87–103.

Caravan P. Protein-targeted gadolinium-based Magnetic Resonance Imaging (MRI) contrast agents: Design and mechanism of action. Acc. Chem. Res. 2009;42:851–862. doi: 10.1021/ar800220p. PubMed DOI

Bonnet C.S., Buron F., Caillé F., Shade Ch.M., Drahoš B., Pellegatti L., Zhang J., Villette S., Helm L., Pichon Ch., et al. Pyridine-based lanthanide complexes combining MRI and NIR luminescence activities. Chem. Eur. J. 2012;18:1419–1431. doi: 10.1002/chem.201102310. PubMed DOI

Wängler C., Wängler B., Eisenhut M., Haberkorn U., Mier W. Improved syntheses and applicability of different DOTA building blocks for multiply derivatized scaffolds. Bioorg. Med. Chem. 2008;16:2606–2616. doi: 10.1016/j.bmc.2007.11.044. PubMed DOI

Rudovsky J., Botta M., Hermann P., Hardcastle K.I., Lukeš I., Aime S. PAMAM dendrimeric conjugates with a Gd-DOTA phosphinate derivative and their adducts with polyaminoacids: The Interplay of global motion, internal rotation, and fast water exchange. Bioconjug. Chem. 2006;17:975–987. doi: 10.1021/bc060149l. PubMed DOI

Jauregui M., Perry W.S., Allain C., Vidler L.R., Willis M.C., Kenwright A.M., Snaith J.S., Stasiuk G.J., Lowe M.P., Faulkner S. Changing the local coordination environment in mono- and bi-nuclear lanthanide complexes through “click” chemistry. Dalton Trans. 2009 doi: 10.1039/B911588A. PubMed DOI

Botta M., Tei L. Relaxivity enhancement in macromolecular and nanosized GdIII-based MRI contrast agents. Eur. J. Inorg. Chem. 2012;12:1945–1960. doi: 10.1002/ejic.201101305. DOI

Pope S.J.A., Kenwright A.M., Boote V.A., Faulkner S. Synthesis and luminescence properties of dinuclear lanthanide complexes derived from covalently linked macrocyclic ligands. Dalton Trans. 2003 doi: 10.1039/B309115E. DOI

Bridger G.J., Skerlj R.T., Hernandez-Abad P.E., Bogucki D.E., Wang Z., Zhou Y., Nan S., Boehringer E.M., Wilson T., Crawford J., et al. Synthesis and structure-activity relationships of Azamacrocyclic C-X-C chemokine receptor 4 antagonists: Analogues containing a single azamacrocyclic ring are potent inhibitors of T-Cell tropic (X4) HIV-1 replication. J. Med. Chem. 2010;53:1250–1260. doi: 10.1021/jm901530b. PubMed DOI

Gupta S.K. Method for inducing chemotaxis in endothelial cells by administering stromal cell derived factor-1alpha. 2002/0107195 A1. U.S. Patent. 2002 August.

Luengo J.I., Price A.T., Shaw A., Wiggall K. CXCR-4 receptor antagonists and thrombopoietin mimetics. WO/2000/066112. WIPO Patent. 2000 Nov 9;

Livramento J.B., Sour A., Borel A., Merbach A.E., Tóth É. A starburst-shaped heterometallic compound incorporating six densely packed Gd3+ ions. Chem. Eur. J. 2006;12:989–1003. doi: 10.1002/chem.200500969. PubMed DOI

Li W.S., Luo J., Chen Z.N. A self-assembly heterotrinuclear gadolinium(III)–iron(II) complex as a MRI contrast agent. Inorg. Chem. Commun. 2011;14:1898–1900. doi: 10.1016/j.inoche.2011.09.006. DOI

Ng C.Y., Motekaitis R.J., Martell A.E. New multidentate ligands. 18. Synthesis of 1,4-Bis(bis(2-aminoethy1)aminomethyl)benzene: Binuclear chelating tendencies and mixed-ligand binuclear chelate formation. Inorg. Chem. 1979;18:2982–2986. doi: 10.1021/ic50201a008. DOI

Barrett D.M.Y., Kahwa I.A., Mague J.T., McPherson G.L. Preparations, crystal structures, and unusual proton NMR characteristics of some phthalimides. J. Org. Chem. 1995;60:5946–5953. doi: 10.1021/jo00123a035. DOI

Kang S.O., Powell D., Day V.W., Bowman-James K. Trapped Bifluoride. Angew. Chem. Int. Ed. 2006;45:1921–1925. doi: 10.1002/anie.200504066. PubMed DOI

Gali H., Prabhu K.R., Karra S.R., Katti K.V. Facile Ring-opening reactions of Phthalimides as a new strategy to synthesize amide-functionalized phosphonates, primary phosphines, and bisphosphines. J. Org. Chem. 2000;65:676–680. doi: 10.1021/jo991067b. DOI

Drahoš B., Kotek J., Císařová I., Hermann P., Helm L., Lukeš I., Tóth É. Mn2+ complexes with 12-membered pyridine based macrocycles bearing carboxylate or phosphonate pendant arm: Crystallographic, thermodynamic, kinetic, redox, and 1H/17O relaxation studies. Inorg. Chem. 2011;50:12785–12801. doi: 10.1021/ic201935r. PubMed DOI

Aime S., Barge A., Bruce J.I., Botta M., Howard J.A.K., Moloney J.M., Parker D., de Sousa A.S., Woods M. NMR, relaxometric, and structural studies of the hydration and exchange dynamics of cationic lanthanide complexes of macrocyclic tetraamide ligands. J. Am. Chem. Soc. 1999;121:5762–5771. doi: 10.1021/ja990225d. DOI

Frisch M.J., Trucks G.W., Schlegel H.B., Scuseria G.E., Robb M.A., Cheeseman J.R., Montgomery J.A., Jr., Vreven T., Kudin K.N., Burant J.C., et al. Gaussian 03, Revision C.02. Gaussian, Inc.; Wallingford, CT, USA: 2004.

Aime S., Gianolio E., Terreno E., Giovenzana G.B., Pagliarin R., Sisti M., Palmisano G., Botta M., Lowe M.P., Parker D. Ternary Gd(III)L-HSA adducts: Evidence for the replacement of inner-sphere water molecules by coordinating groups of the protein. Implications for the design of contrast agents for MRI. J. Biol. Inorg. Chem. 2000;5:488–497. PubMed