A Bisphosphonate Monoamide Analogue of DOTA:  A Potential Agent for Bone Targeting

• Published in: Journal of the American Chemical Society 2005-11, Vol.127 (47), p.16477-16485
• Main Authors: Kubíček, Vojtěch, Rudovský, Jakub, Kotek, Jan, Hermann, Petr, Vander Elst, Luce, Muller, Robert N, Kolar, Zvonimir I, Wolterbeek, Hubert Th, Peters, Joop A, Lukeš, Ivan
• Format: Article
• Language: English
• Subjects: Adsorption; Amides - chemistry; Amides - pharmacokinetics; Binding, Competitive; Biocompatible Materials - chemistry; Biological and medical sciences; Bone and Bones - chemistry; Chelating Agents - chemistry; Chelating Agents - pharmacokinetics; Chemistry; Contrast media. Radiopharmaceuticals; Coordination compounds; Diphosphonates - chemistry; Diphosphonates - pharmacokinetics; Durapatite - chemistry; Exact sciences and technology; Gadolinium - chemistry; Heterocyclic Compounds, 1-Ring - chemistry; Heterocyclic Compounds, 1-Ring - metabolism; Inorganic chemistry and origins of life; Lanthanoid Series Elements - chemistry; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Medical sciences; Models, Biological; Molecular Structure; Pharmacology. Drug treatments; Preparations and properties
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja054905u

A new macrocyclic DOTA-like ligand (BPAMD) for bone imaging and therapy containing a monoamide bis(phosphonic acid) bone-seeking group was designed and synthesized. Its lanthanide(III) complexes were prepared and characterized by 1H and 31P NMR spectroscopy. The Gd(III)−BPAMD complex was investigated in detail by 1H and 17O relaxometric studies to inspect parameters relevant for its potential application as an MRI contrast agent. Sorption experiments were conducted with Gd(III) and Tb(III) complexes using hydroxyapatite (HA) as a model of bone surface. Very effective uptake of the Gd−BPAMD complex by the HA surface was observed in NMR experiments. Radiochemical studies with the (160Tb−BPAMD)−HA system proved the sorption to be remarkably fast and strong on one hand and fully reversible on the other hand. The strong (Gd−BPAMD)−HA interaction was also supported by 1H NMRD measurements in the presence of a hydroxyapatite slurry, which showed an increase of the rotational correlation time upon adsorption of the complex on the HA surface, resulting in a significant relaxivity enhancement. The amide-bis(phosphonate) moiety is the only factor responsible for the binding of the complex to HA.