[en] Lanthanide complexes of DOTA derivatives 2a (BPAMD) and 2b (BPAPD), having a monoamide pendant arm with a bis(phosphonate) moiety, were comparatively tested for application in MRI, radiotherapy, and bone pain palliation. H-1, P-31, and O-17 NMR spectroscopy show that they are nine-coordinated, with one water molecule in the first coordination sphere of the Ln(III) ion. The bis(phosphonate) moieties are not coordinated to the lanthanide and predominantly mono- and diprotonated at physiological pH. The parameters governing the longitudinal relaxivities of the Gd complexes are similar to those of other monoamides of DOTA reported in the literature. Upon adsorption on hydroxyapatite, the relaxivities at 20 MHz and 25 degrees C of Gd-2a and Gd-2b were 22.1 and 11 s(-1) mM(-1), respectively. An in vivo gamma-ray imaging study showed that the Lu-177 complexes of 2a and 2b have a high affinity for bones, particularly for growth plates and teeth with a prolonged retention.
Disciplines :
Radiology, nuclear medicine & imaging Chemistry
Author, co-author :
Vitha, T.
Kubicek, V.
Hermann, P.
Vander Elst, Luce ; Université de Mons > Faculté de Médecine et de Pharmacie > Biochimie métabolique et moléculaire
Muller, Robert ; Université de Mons > Faculté de Médecine et de Pharmacie > Chimie générale, organique et biomédicale
Kolar, Z.I.
Wolterbeek, H.T.
Breeman, W.A.P.
Lukes, I.
Peters, J. A.
Language :
English
Title :
Lanthanide(III) complexes of bis(phosphonate) monoamide analogues of DOTA: Bone-seeking agents for imaging and therapy
Publication date :
01 January 2008
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
Publisher :
American Chemical Society, United States - District of Columbia
Merbach, A. E., Tóth, E. Eds. The chemistry of contrast agents in medical magnetic resonance imaging; John Wiley and Sons: Chichester, 2001.
Caravan, P.; Ellison, J. J.; McMurry, T. J.; Laufer, R. B. Gadolinium(III) chelates as MRI contrast agents: Structure, dynamics, and applications. Chem. Rev. 1999, 99, 2293-2352.
Jacques, V.; Desreux, J. F. New classes of MRI contrast agents. Top. Curr. Chem. 2002, 221, 123-164.
Aime, S.; Geninatti Crich, S.; Gianolio, E.; Giovenzana, G. B.; Tei, L.; Terreno, E. High sensitivity lanthanide(III) based probes for MR-medical imaging. Coord. Chem. Rev. 2006, 250, 562-1579.
Bagi, C. M. Targeting of therapeutic agents to bone to treat metastatic cancer. Adv. Drug Delivery Rev. 2005, 57, 995-1010.
Adzamli, I. K.; Gries, H.; Johnson, D.; Blau, M. Development of phosphonate derivatives of gadolinium chelates for NMR imaging of calcified soft tissues. J. Med. Chem. 1989, 32, 139-144.
Schwochau, K. Technetium chemistry and radiopharmaceutical applications. Wiley-VCH: Weinheim, Germany, 2000.
Fleisch, H. Bisphosphonates in bone disease. Academic Press: London, UK, 2000.
Alves, F. C.; Donato, P.; Sherry, A. D.; Zaheer, A.; Zhang, S.; Lubag, A. J. M.; Merritt, M. E.; Lenkinski, R. E.; Frangioni, J. V.; Neves, M.; Prata, M. I. M.; Santos, A. C.; de Lima, J. J. P.; Geraldes, C. F. G. C. Silencing of phosphonate-gadolinium magnetic resonance imaging contrast by hydroxyapatite binding. Invest. Radiol. 2003, 38, 750-760.
Bligh, S. W. A.; Harding, C. T.; McEwen, A. B.; Adler, P. J.; Kelly, J. D.; Marriott, J. A. Synthesis, characterization and comparative study of aminophosphonate chelates of gadolinium(III) ions as magnetic resonance imaging contrast agents. Polyhedron 1994, 13, 1937-1943.
Adzamli, I. K.; Johnson, D.; Blau, M. Phosponate-modified GdDTPA complexes II. Evaluation in a rat myocardial infarct model. Invest. Radiol. 1991, 26, 143-148.
Adzamli, I. K.; Blau, M. Phosponate-modified GdDTPA complexes I. NMRD study of the solution behavior of new tissue-specific contrast agents. Magn. Reson. Med. 1991, 17, 141-148.
Adzamli, I. K.; Blau, M.; Pfeffer, M. A.; Davis, M. A. Phosponate-modified GdDTPA complexes. III. The detection of myocardial infarction by MRI. Magn. Reson. Med. 1993, 29, 505-511.
Greb, W.; Blum, M.; Roth, M. Contrast medium for using in image-producing methods. PCT WO 03/097074, 2003.
Kubíček, V; Rudovský, J.; Kotek, J.; Hermann, P.; Vander Elst, L.; Muller, R. N.; Kolar, Z. I.; Wolterbeek, H. T.; Peters, J. A.; Lukeš, I. A. Bisphosphonate monoamide analogue of DOTA: A potential agent for bone targeting. J. Am. Chem. Soc. 2005, 127, 16477-16485.
Vitha, T.; Kubíček, V.; Hermann, P.; Kolar, Z. I.; Wolterbeek, H. T.; Peters, J. A.; Lukeš, I. Complexes of DOTA-bisphosphonate conjugates - Probes for determination of adsorption capacity and affinity constants of hydroxyapatite. Langmuir, in press.
Aime, S.; Botta, M.; Fasano, M.; Marques, M. P. M.; Geraldes, C. F. G. C.; Pubanz, D.; Merbach, A. E. Conformational and coordination equilibria on DOTA complexes of lanthanide metal ions in aqueous solution studied by 1H-NMR spectroscopy. Inorg. Chem. 1997, 36, 2059-2068.
Aime, S.; Botta, M.; Ermondi, G. Paramagnetic water proton relaxation enhancement - from contrast agents in MRI to reagents for quantitative in vitro assays. Inorg. Chem. 1992, 31, 4291-4299.
Howard, J. A. K.; Kenwright, A. M.; Molonney, J. M.; Parker, D.; Port, M.; Navet, M.; Rousseau, O.; Woods, M. Structure and dynamics of all of the stereoisomers of europium complexes of tetra(carboxyethyl) derivatives of dota: ring inversion is decoupled from cooperative arm rotation in the RRRR and RRRS isomers. Chem. Commun. 1998, 13, 1381-1382.
Bleaney, B. Nuclear magnetic resonance shifts in solution due to lanthanide ions. J. Magn. Reson. 1972, 8, 91-100.
Bleaney, B.; Dobson, C. M.; Levine, B. A.; Martin, R. B.; Williams, R. J. P.; Xavier, A. V. Origin of lanthanide nuclear magnetic resonance shifts and their uses. J. Chem. Soc., Chem. Commun. 1972, 791-793.
Golding, R. M.; Halton, M. P. Theoretical study of the nitrogen-14 and oxygen-17 NMR shifts in lanthanide complexes. Aust. J. Chem. 1972, 25, 2577-2581.
Golding, R. M.; Pyykkö, P. Theory of pseudocontact NMR shifts due to lanthanide complexes. Mol. Phys. 1973, 26, 1389-1396.
Pinkerton, A. A.; Rossier, M.; Spiliadis, S. Lanthanide-induced contact shifts. The average electron spin polarization, theory and experiment. J. Magn. Reson. 1985, 8, 420-425.
Peters, J. A.; Huskens, J.; Raber, D. J. Lanthanide induced shifts and relaxation rate enhancements. Prog. Nucl. Magn. Reson. Spectrosc. 1996, 28, 283-350.
Alpoim, M. C.; Urbano, A. M.; Geraldes, C. F. G. C.; Peters, J. A. Determination of the number of inner-sphere water molecules in lanthanide(III) polyaminocarboxylate complexes. J. Chem. Soc., Dalton Trans. 1992, 463-467.
Djanashvili, K.; Peters, J. A. How to determine the number of inner-sphere water molecules in lanthanide(III)-complexes by 17O NMR spectroscopy. A technical note. Contrast Media Mol. Imaging 2007, 2, 67-71.
Dyba, M.; Kozlowski, H.; Tlalka, A.; Leroux, Y.; El Manouni, D. Oxovanadium(IV) complexes of 1-hydroxyalkane-1,1-diyldiphosphonic acids. Pol. J. Chem. 1998, 72, 1148-1153.
Martell, A. E.; Smith, R. M. Critical stability constants; Plenum Press: New York, 1974-1989, Vols. 1-6; NIST Standard Reference Database 46 (Critically Selected Stability Constants of Metal Complexes), version 7.0, 2003.
Kubíček, V.; Kotek, J.; Hermann, P.; Lukeš, I. Aminoalkylbis(phosphonates): their complexation properties in solution and in the solid state. Eur. J. Inorg. Chem. 2007, 2, 333-344.
Lebdušková, P.; Kotek, J.; Hermann, P.; Vander Elst, L.; Muller, R. N.; Lukeš, I.; Peters, J. A. A gadolinium(III) complex of a carboxylic-phosporus acid derivative of diethylenetriamine covalently bound to inulin as a new potential macromolecular MRI contrast agent. Bioconjugate Chem. 2004, 15, 881-889.
Powell, D. H.; Dhubhghaill, O. M. N.; Pubanz, D.; Helm, L.; Lebedev, Y. S.; Schlaepfer, W.; Merbach, A. E. Structural and dynamic parameters obtained from 17O NMR, EPR, and NMRD studies of monomeric and dimeric Gd 3+ complexes of interest in magnetic resonance imaging: An integrated and theoretically self-consistent approach. J. Am. Chem. Soc. 1996, 118, 9333-9346.
Aime, S.; Botta, M.; Garino, E.; Geninatti Crich, S.; Giovenzana, G.; Pagliarin, R.; Palmisano, G.; Sisti, M. Non-covalent conjugates between cationic polyamino acids and Gd(III) chelates: A route for seeking accumulation of MRI-contrast agents at tumor targeting sites. Chem. - Eur. J. 2000, 6, 2609-2617.
Aime, S.; Botta, M.; Fasano, M.; Terreno, E. Lanthanide(III) chelates for NMR biomedical applications. Chem. Soc. Rev. 1998, 27, 19-29.
Breeman, W. A. P.; van der Wansem, K.; Bernard, B. F.; van Gameren, A.; Erion, J. L.; Visser, T. J.; Krenning, E. P.; de Jong, M. The addition of DTPA to [177Lu-DOTA0,Tyr3]octreotate prior to administration reduces rat skeleton uptake of radioactivity. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 312-315.
Breeman, W. A. P.; de Jong, M. T.; de Blois, E.; Bernard, B. F.; de Jong, M; Krenning, E. P. Reduction of skeletal accumulation of radioactivity by co-injection of DTPA in [90Y-DOTA0,Tyr3] octreotide solutions containing free 90Y3+. Nucl. Med. Biol. 2004, 31, 821-824.
Thakral, C.; Alhariri, J.; Abraham, J. L. Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications. Contrast Media Mol. Imaging 2007, 2, 199-205.
Dadabhoy, A.; Faulkner, S.; Sammes, P. G. Long wavelength sensitizers for europium(III) luminescence based on acridone derivatives. J. Chem. Soc., Perkin Trans. 2 2002, 2, 348-357.
Winckler, W.; Pieper, T.; Keppler, B. K. Preparation of octaethyl-3-amino-pentane-1,1,5,5-tetrakisphosphonate by catalytic hydrogenation of the corresponding 3-nitro-compound. Phosphorus, Sulfur Silicon Relat Elem. 1996, 112, 137-141.
Zitha-Bovens, E.; Vander Elst, L.; Muller, R. N.; van Bekkum, H.; Peters, J. A. Relaxivity studies on a gadolinium(III) complex of a macrocyclic DTPA derivative. Eur. J. Inorg. Chem. 2001, 12, 3101-3105.
Vold, R. L.; Waugh, J. S.; Klein, M. P.; Phelps, D. E. Measurement of spin relaxation in complex systems. J. Chem. Phys. 1968, 48, 3831-3832.
Meiboom, S.; Gill, D. Modified spin-echo method for measuring nuclear relaxation times. Rev. Sci. Instrum. 1958, 29, 688-691.
Corsi, D. M.; Platas-Iglesias, C.; van Bekkum, H.; Peters, J. A. Determination of paramagnetic lanthanide(III) concentrations from bulk magnetic susceptibility shifts in NMR spectra. Magn. Reson. Chem. 2001, 39, 723-726.
Scientist for Windows, version 2.01, Micromath, Inc.: Salt Like City, UT, 1995.
Kývala, M.; Lukeš, I. International Conference Chemometrics '95, Pardubice, Czech Republic, 1995, p. 63; the full version of OPIUM is available (free of charge) on http://www.natur.cuni.cz/~kyvala/ opium.html.
