Dinuclear DOTA‐Based GdIII Chelates – Revisiting a Straightforward Strategy for Relaxivity Improvement. Issue 9 (18th February 2015)

• Record Type: Journal Article
• Authors: Fontes, André; Karimi, Shima; Helm, Lothar; Yulikov, Maxim; Ferreira, Paula M.; André, João P.
• Is Part Of: European journal of inorganic chemistry. Issue 9(2015)
• Page Start: 1579
• Page End: 1591
• Publication Date: 2015-02-18
• Subjects: Chelates -- Imaging agents -- Macrocycles -- Dinuclear complexes -- ­Gadolinium; Chemistry, Inorganic -- Periodicals; Organometallic chemistry -- Periodicals; Bioinorganic chemistry -- Periodicals; Solid state chemistry -- Periodicals; 546
• DOI: 10.1002/ejic.201403159
• Languages: English
• ISSNs: 1434-1948

Abstract

Abstract: The need for magnetic resonance imaging (MRI) contrast agents with improved relaxivity maintains the development of new Gd III chelates as an intensive and demanding field of research. In this work, we introduce the new dimeric chelators bis{1, 4, 7, 10‐tetraazacyclododecane‐1‐[(6‐amino)hexanoic]‐4, 7, 10‐triacetic acid}adipate [L2, bis(DOTA‐AHA)adipate] and bis{1, 4, 7, 10‐tetraazacyclododecane‐1‐[(6‐amino)hexanoic]‐4, 7, 10‐triacetic acid}1, 3‐phenyldiacetate [L3, bis(DOTA‐AHA)1, 3‐phenyldiacetate], which are based on the bifunctional ligand 1, 4, 7, 10‐tetraazacyclododecane‐1‐[(6‐amino)hexanoic]‐4, 7, 10‐triacetic acid (L1, DOTA‐AHA). Their Gd III chelates were studied by variable‐temperature 1 H nuclear magnetic relaxation dispersion (NMRD) and 17 O NMR spectroscopy to measure their relaxivities and the parameters that govern them. The rates of exchange of inner‐sphere water from the monomer GdL1 and from the two dinuclear chelates Gd2 L2 and Gd2 L3 are very similar ( 298 k ex ≈ 6.5 × 10 6 s –1 ) and slightly faster than that for [Gd(DOTA)H2 O] – ( 298 k ex = 4.1 × 10 6 s –1 ). All three compounds form weakly bound aggregates with equilibrium constants 298 K of 2.9, 15.6, and 14.6 for GdL1, Gd2 L2, and Gd2 L3, respectively. Even though the aggregates contain only 10 to 15 % of the total amount of Gd III ions, a marked increase in relaxivity between 30 and 100 MHz is observed. Furthermore, the distance between the two Gd III centers in the dinuclear compounds has been determined by double electron–electron resonance (DEER) spectroscopy experiments and by molecular modeling studies, which afforded comparable distances. The linkers between the chelating moieties allow Gd III –Gd III distances of ca. 3.0 nm for the completely stretched linker conformation and less than 1.9 nm for the conformation with the metal centers at a closer distance. These metal‐to‐metal distances by themselves cannot explain the considerably long tumbling times of the chelates in solution. Only a model consistent with some level of aggregation for the dinuclear chelates in aqueous solution could satisfactorily explain our results. Abstract : Two DOTA‐based dimeric chelators are developed, and their dinuclear Gd III chelates are studied by variable‐temperature 1 H nuclear magnetic relaxation dispersion (NMRD) and 17 O NMR spectroscopy. The distance between the Gd III centers is determined by double electron–electron resonance and by molecular modeling. Only a model with some level of aggregation could satisfactorily explain our results.