Lanthanide(III) Complexes of Bis(phosphonate) Monoamide Analogues of DOTA: Bone-Seeking Agents for Imaging and Therapy

• Published in: Journal of medicinal chemistry 2008-02, Vol.51 (3), p.677-683
• Main Authors: Vitha, Tomáš, Kubíček, Vojtěch, Hermann, Petr, Elst, Luce Vander, Muller, Robert N, Kolar, Zvonimir I, Wolterbeek, Hubert T, Breeman, Wouter A.P, Lukeš, Ivan, Peters, Joop A
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacokinetics; Animals; Biological and medical sciences; Bone and Bones - diagnostic imaging; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Chelating Agents - pharmacokinetics; Contrast media. Radiopharmaceuticals; Diphosphonates - chemical synthesis; Diphosphonates - chemistry; Diphosphonates - pharmacokinetics; Gadolinium; Heterocyclic Compounds, 1-Ring - chemical synthesis; Heterocyclic Compounds, 1-Ring - chemistry; Heterocyclic Compounds, 1-Ring - pharmacokinetics; Lanthanum; Ligands; Lutetium; Male; Medical sciences; Pharmacology. Drug treatments; Radioisotopes; Radionuclide Imaging; Rats; Rats, Inbred Lew; Structure-Activity Relationship; Tissue Distribution
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm7012776

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. 1H, 31P, and 17O 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 °C of Gd-2a and Gd-2b were 22.1 and 11 s−1 mM−1, respectively. An in vivo γ-ray imaging study showed that the 177Lu complexes of 2a and 2b have a high affinity for bones, particularly for growth plates and teeth with a prolonged retention.