Synthesis and characterization of lanthanide complexes of DO3A-alkylphosphonates

Ilgar Mamedov; Anurag Mishra; Goran Angelovski; Hermann A. Mayer; Lars-Olof Pålsson; David Parker; Nikos K. Logothetis

doi:10.1039/B711351J

Synthesis and characterization of lanthanide complexes of DO3A-alkylphosphonates†

Ilgar Mamedov,‡^a Anurag Mishra,‡^a Goran Angelovski,*^a Hermann A. Mayer,*^b Lars-Olof Pålsson,^c David Parker^c and Nikos K. Logothetis^ad

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^a Department for Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics, Spemannstr. 38, 72076 Tübingen, Germany
E-mail: goran.angelovski@tuebingen.mpg.de
Fax: +49 7071 601 652
Tel: +49 7071 601 916

^b Department for Inorganic Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
E-mail: hermann.mayer@uni-tuebingen.de
Fax: +49 7071 29 2436
Tel: +49 7071 2976 229

^c Department of Chemistry, Durham University, South Road, Durham, UK

^d Imaging Science and Biomedical Engineering, University of Manchester, Manchester, UK

Abstract

Eight DO3A-based lanthanide(III) complexes bearing ester protected and unprotected phosphonate groups at variable distances from the macrocyclic moiety have been synthesized and analyzed. The ligands were made by straightforward four-step synthetic procedures and purified with preparative RP-HPLC, after which they were used to prepare gadolinium(III) and europium(III) complexes. Relaxometric experiments were performed on the Gd(III) complexes at 300 MHz, varying the pH of the solutions or the concentration of human serum albumin (HSA). It was found that when the pH of the medium was changed from neutral to pH 4 the longitudinal relaxivity of GdDO3A-ethylphosphonate and GdDO3A-propylphosphonate complexes increased by 50% and 60%, respectively. Diethyl esters of these complexes did not change longitudinal relaxivity in the same pH range but their transverse relaxivity increased upon binding to HSA. ³¹P NMR experiments on Eu(III) complexes showed a change in the chemical shift of both acid complexes in the same region where the highest relaxivity changes were observed and proved the stability of the complexes in the investigated pH range, while no shift was observed for the diester complexes. Luminescence studies on europium(III) complexes additionally supported observations obtained by NMR methods. The change in the form of the luminescence emission spectra, and the reduction in the q value upon addition of HSA proved the ternary adduct formation between the charge neutral diester complexes and HSA. Similarly, the change in the emission spectra showing a phosphonate bound structure at pH 7 to a species where the phosphonate oxygen is not coordinated at pH 4 in parallel with the increase of q value is supporting the hypothesis that the deprotonation of phosphonates is the main reason for the distinct relaxivity change from slightly acidic to the neutral solution media.

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Synthesis and characterization of lanthanide complexes of DO3A-alkylphosphonates†

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Synthesis and characterization of lanthanide complexes of DO3A-alkylphosphonates

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