Highly Soluble Tris-hydroxypyridonate Gd(III) Complexes with Increased Hydration Number, Fast Water Exchange, Slow Electronic Relaxation, and High Relaxivity

Abstract

The design, synthesis, and relaxivity properties of highly soluble TACN-capped trishydroxypyridonate Gd(III) complexes are presented. Molecular mechanics modeling was used to help design a complex capable of possessing three water molecules in the inner metal coordination sphere, an attractive property for high-relaxivity MRI contrast agents. The measured relaxivities of 13.1 and 12.5 mM -1 s -1 (20 MHz, 298 K) for two TACN-capped complexes are among the highest known relaxivities of low-molecular weight Gd complexes and are consistent with three coordinated waters, an extremely fast water exchange rate and long electronic relaxation time. Luminescence measurements to confirm the number of coordinated water molecules for the first time in the HOPO series are also discussed.Magnetic Resonance Imaging (MRI) is a powerful diagnostic technique in modern medicine, and the emergence of new instrumentation and applications invites the production of contrast agents with enhanced imaging capabilities. Contrast agents are evaluated on the basis of their proton relaxivities (r 1p ), and current values for commercial agents (based on poly-(aminocarboxylate) ligands) are small (r 1p = 4 -5 mM -1 s -1 ; 20 MHz and 298 K) compared to what is theoretically possible. 2,3 To obtain the high relaxivities predicted by theory, there are several parameters that must be optimized, including: q, the number of bound waters, τ m , the mean water residence time, τ s , the metal electronic relaxation time, Correspondence to: Kenneth N. Raymond.raymond@socrates.berkeley.edu . Supporting Information Available: Detailed synthesis and characterization of 3 and of TACN-1,2-HOPO, temperature dependence of the paramagnetic contribution to the water 17 O NMR transverse relaxation rate (R 2p ) for 3, and details of the luminescence and stability measurements. This information is available free of charge via the internet at http://pubs.acs.org. Here we report stable, soluble complexes with optimal hydration, water exchange, and electronic relaxation properties, representing major advances toward that goal. NIH Public AccessIn 1995, a Gd complex was described that showed promise as a contrast agent, Gd(TREN-1-Me-3,2-HOPO)(H 2 O) 2 (1, Figure 1). 6 The r 1p value of this hexadentate hydroxypyridinone-(HOPO) based complex was measured as twice that of commercial agents due largely to the complex's increased number of bound water molecules (q of 2 as compared to 1 for commercial agents). Importantly, the stability of this complex (a critical factor for in vivo use 7 ) is higher than that of clinical agents despite the lower ligand denticity and increase in q. Since this initial report, a series of complexes, all based on the tripodal TREN (tris-(2-aminoethyl)-amine) scaffold, has been prepared in an attempt to optimize the proton relaxation parameters and increase aqueous solubility. 8 Those complexes that show the most promising relaxometric and solubility properties rely on the TREN-capped heteropodal bis-HOPO-TAM design (2, Figure 1). For exa...

High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents1

“…Higher relaxivities can be attained in these cases by using Gd chelates with smaller τ M values (1-2 ns) optimal for higher field strengths, in conjunction to rigid linkers. The use of the Gd-TACN-HOPO-based complexes with such optimal water-exchange rates and a higher number of inner sphere water molecules (q=3) 33 should enhance the obtained relaxivities, as predicted in this study. The generation of additional capsid conjugates that possess these properties is currently in progress in our laboratories.…”

“…The q value is reliably estimated by analysis of the NMRD profiles and by comparison of the relaxivity data for a large series of related complexes. 30 The validity of the relaxometric evaluation of the hydration number has been confirmed through the direct measurement of q by luminescence in the case of EuTACN-1,2-HOPO (q = 3) 33 and Eu-H(2,2)-1,2-HOPO (q = 1). 39 The NMRD profile fits for the 4 conjugates were obtained by fixing q to 2.…”

High‐Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging

“…Utilizing the known oxophilicity of lanthanides, purely oxygen donor ligands such as hydroxypyridinone (both the 3,2-HOPO and 1,2-HOPO isomers), maltol (MAM), and terephthalamide (TAM) have been developed and explored as chelators expected to form stable Gd complexes. The obtained complexes (with two [46] or three [51] inner-sphere water molecules) have been examined as candidates for next generation agents. The feasibility of applying these O donor ligands as practical agents has been proven successfully in vivo.…”

“…In a recent report, triazacyclononane (TACN) was used as a ligand cap to produce both tris-3,2-and 1,2-HOPO complexes (13 and 14). [51] Molecular modelling studies predicted that the larger cap (relative to TREN) would accommodate three inner-sphere water molecules, and subsequent relaxometric and luminescent characterization revealed a successful design strategy. Relaxivities were found to be 13.1 and 12.5 mM -1 s -1 (20 MHz, 298 K, pH 7), values that remained high at field strengths above 0.5 T. The stabilization of the q = 3 complex in this case is accomplished without the need for the asymmetric bis-HOPO-TAM motif.…”

1,2-Hydroxypyridonates as Contrast Agents for Magnetic Resonance Imaging: TREN-1,2-HOPO

“…Contrary to several well studied 3,2-HOPO chelates, only TREN-1,2-HOPO 15 and TACN-1,2-HOPO 6 have been described as 1,2-HOPO chelates for MRI contrast agents. Comparison of the solid state structure and NMRD profile of Gd-TREN-1,2-HOPO with Gd-TREN-3,2-HOPO led to the conclusion that these complexes behave very similarly in solution.…”